ES2259707T3 - OXAZOLO AND FUROPIRIMIDINAS AND ITS USE IN DRUGS MEDICINES. - Google Patents

Abstract

The invention relates to pharmaceutically acceptable compounds of formula I, wherein the radicals have the significances given in the description. Compounds of formula I are useful against tumor diseases

Description

Oxazolo and furopyrimidines and their use in anti-tumor medications

Summary of the invention

The invention relates to oxazolo derivatives and / or furopyrimidines, intermediates and procedures for their production, pharmaceutical formulations comprising these compounds, and their use as medicines or in the preparation of medicines.

Background of the invention

Tumor diseases are one of the causes most important of death in industrialized countries. They have made great efforts to provide effective compositions and Methods for the treatment of tumors. Due in particular to large number and large variation of possible diseases tumor, there is a constant need for new compounds pharmacologically active and compositions, which, due to their active ingredients, are well suited to treat so many tumor diseases as possible or alternatively are suitable for treating specific tumor diseases. Further, there are various proliferative diseases or diseases based in a defective or non-existent physiological regulation.

US 6096749A describes pyrrolo-pyrimidines as EGF inhibitors.

Detailed description of the invention

The invention relates to a compound of formula I,

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one

in which X or means nitrogen, or a carbon atom that carries a radical TO;

A means hydrogen or -COOW, in which W is hydrogen or alkyl, aryl, heterocyclyl or cycloalkyl, as which of these radicals is unsubstituted or replaced;

Y is NR ', S or O, according to which R' means hydrogen or alkyl;

R means aryl, heterocyclyl, cycloalkyl, aryl-alkyl, heterocyclyl-alkyl or cycloalkyl-alkyl, according to which each of these radicals are unsubstituted or substituted; or is COOR ', COR' or CONR'R '', in which R 'and R' ', independently of each other, are hydrogen or alkyl, aryl, heterocyclyl, cycloalkyl, aryl-alkyl, heterocyclyl-alkyl or cycloalkyl-alkyl, according to which each of these radicals are unsubstituted or substituted; Y

Q is aryl, aryl-alkyl, heterocyclyl, heterocyclyl-alkyl, cycloalkyl or cycloalkyl-alkyl, which are respectively substituted or unsubstituted;

or a salt thereof, as well as products intermediates and procedures for their production, pharmaceutical formulations comprising these compounds as well as its use as medicines or in the preparation of medicines (pharmaceutical preparations).

Preferably, the general terms previously used in this document and hereafter in this document they have, within the context of this description, the following meanings, unless indicated contrary:

The "lower" prefix indicates a radical that has up to and including a maximum of 7, especially up to e including a maximum of 4 carbon atoms, the radicals being in question not branched or branched with simple branching or multiple.

When the plural form is used to compounds, salts, and the like, this is considered to mean also a single compound, salt, or the like ("one / one") as an indefinite article or as a number).

The asymmetric carbon atoms that are optionally present in the substituents may exist in the configuration (R), (S) or (R, S), preferably in the configuration (R) or (S). Thus, the present compounds may exist as mixtures of isomers or as pure isomers, preferably as pure diastereoisomers or enantiomers.

Alkyl is preferably an alkyl radical with 1 to 20, especially 1 to 10, carbon atoms, preferably lower alkyl, especially methyl. The alkyl It is not branched or has a single or multiple branching. He alkyl is unsubstituted or substituted by one or more, preferably up to three, especially 1 or 2, substituents, selected, independently of each other, from the mentioned below as substituents for aryl.

The lower alkyl is not branched or has a single or multiple branching, and is in particular methyl or ethyl, or also n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.

Aryl is preferably an aromatic radical with from 6 to 18, preferably from 6 to 14 carbon atoms, especially phenyl, naphthyl, fluorenyl or phenanthrenyl, as which aryl, especially the mentioned radicals, can be not substituted or substituted by one or more substituents, preferably up to three, mainly one or two substituents, specially selected from amino; lower alkylamino; N, N-di-lower alkylamino; amino lower alkyl; alkylamino lower-lower alkyl; N, N-di-alkylamino lower-lower alkyl; lower alkanoylamino, especially acetylamino; halogen, especially fluorine, chlorine or bromine; lower alkyl, especially methyl or also ethyl or propyl; lower alkenyl; phenyl; naphthyl; halogen-lower alkyl, especially trifluoromethyl; hydroxyl; lower alkoxy, especially methoxy or also ethoxy; lower alkenyloxy; phenyl-lower alkoxy, especially benzyloxy; lower alkanoyloxy; carbamoyl-alkoxy lower; lower carboxy-alkoxy; phenyl-alkoxycarbonyl lower-lower alkoxy; mercapto; nitro; carboxyl; lower alkoxycarbonyl; phenyl-lower alkoxycarbonyl; cyano; alkoxy C_ {8} -C_ {12}, especially n-decyloxy; carbamoyl; lower alkylcarbamoyl, such as N-methyl or N-tert-butylcarbamoyl; N, N-di-lower alkylcarbamoyl; N-monkey or N, N-diphenyl alkylcarbamoyl lower; lower alkanoyl, such as acetyl; phenyloxy; halogen-lower alkyloxy, such as trifluoromethoxy or 1,1,2,2-tetrafluoroethyloxy; lower alkoxycarbonyl, such as ethoxycarbonyl; lower alkylpiperazinylcarbonyl; morpholinylcarbonyl; lower alkylpiperazinyl-lower alkyl; lower morpholinyl alkyl; lower alkyl mercapto, such as methylmercapto; halogen lower alkylmercapto, such as trifluoromethylmercapto; hydroxy-alkyl lower, such as hydroxymethyl or 1-hydroxymethyl; lower alkanesulfonyl, such as methanesulfonyl; halogen-lower alkanesulfonyl, such as trifluoromethanesulfonyl; phenylsulfonyl; dihydroxyboro (-B (OH) 2); lower alkylpyrimidinyl, such as 2-methylpyrimidin-4-yl; oxazolyl, such as oxazol-5-yl; lower alkyldioxolanyl, such as 2-methyl-1,3-dioxolan-2-yl; pyrazolyl, such as 1H-pyrazol-3-yl; lower alkylpyrazolyl, such as 1-methylpyrazol-3-yl; lower alkylenedioxy attached to two adjacent carbon atoms, such as methylenedioxy; pyridyl; piperazinyl; alkylpiperazinyl lower; morpholinyl; phenylamino or phenyl-lower alkylamino either unsubstituted or well substituted in the phenyl moiety by halogen, lower alkyl, hydroxyl, lower alkanoyloxy, lower alkoxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N, N-lower dialkylcarbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N, N-di-lower alkylamino or by trifluoromethyl; or a radical of formula R 3 -S (O) m -, in which R 3 it is lower alkyl and m is 0, 1 or 2. In a preferred embodiment of the invention aryl which is substituted by one or more substituents is, in particular, alkylpiperazinylcarbonylphenyl lower, morpholinylcarbonylphenyl, N, N-dialkylcarbamoylphenyl lower, lower alkylpiperazinyl-lower alkylphenyl, morpholinyl-lower alkylphenyl or N, N-dialkylamino lower-lower alkylphenyl.

Halogen is especially fluorine, chlorine, bromine, or iodine, in particular fluorine or chlorine.

Halogen-lower alkyl is methyl or ethyl substituted in particular by a halogen, such as fluorine or chlorine, especially methyl fluoride or chloride of methyl

Lower hydroxyalkyl in particular alkyl lower which is terminally substituted by hydroxyl, preferably hydroxymethyl.

Heterocyclyl is preferably a radical entirely saturated, partially saturated or unsaturated and is preferably monocyclic, or also bi- or tricyclic; preferably it has 1 to 20, especially 1 to 14 atoms of ring, in which one or more, especially one to four, mainly one or two of the ring atoms present at least in the ring that is attached to the remaining radical of the compound of formula I, and / or in additional rings, when present, are heteroatoms specially selected from the group comprising nitrogen, oxygen and sulfur, in which heteroaryl is not substituted or substituted by one or more selected substituents, independently of each other, from those mentioned as substituents for aryl; and is specially selected from the group which comprises pyrrolidinyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, chromanyl, isochromanyl, imidazolyl, thienyl, furyl, pyranyl, tiantrenyl, isobenzofuranyl, benzofuranyl, chromenyl, 2H-pyrrolyl, pyrrolyl, benzimidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, triazolyl, tetrazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrinyl and furazanyl, so these radicals can be not substituted or substituted by one to three, preferably one or two of the substituents mentioned as substituents for aryl, which can be independently selected from each other. The more preferably Q is pyridyl or indolyl.

Cycloalkyl is preferably of C 13 -C 12 -, especially cycloalkyl of C 3 -C 8 -, and is in particular cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; and is unsubstituted or replaced by one or more, especially one to three, preferably one or two of the substituents mentioned, independently of each other, as substituents for aryl

Arylalkyl is preferably aryl-lower alkyl, for example, arylmethyl, by which aryl is preferably defined as above and is not substituted or substituted as described above.

Heterocyclylalkyl is preferably heterocyclyl-lower alkyl, for example heterocyclylmethyl, whereby heterocyclyl is defined preferably as above and is unsubstituted or substituted as described above.

Cycloalkylalkyl is preferably cycloalkyl-lower alkyl, for example cycloalkylmethyl: by which cycloalkyl is defined preferably as above and is unsubstituted or substituted as described above.

A carbon atom that carries a radical A has the formula C (A).

Preference is given to the compounds of formula I, in which X means nitrogen. On the other hand, it also occurs preference to the compounds of the formula I, in which X means a carbon atom that carries a radical A, especially in which X means CH.

The salts are mainly the salts pharmaceutically acceptable compounds of formula I. They can salt formation provided salt forming groups are present in a compound of formula I. Salts of compounds of formula I are in particular acid addition salts (if any present a basic group in the relevant compound of formula I, such as amino or imino), or salts with cations or bases (if it is present an acid group, such as carboxyl, in the compound relevant of formula I); when several groups are present salt formers, internal salts may also be present or mixed salts

Such salts are formed, for example, as salts of acid addition, preferably with organic acids or inorganic, from compounds of formulas I with an atom of basic nitrogen, especially pharmaceutically salts acceptable. Suitable inorganic acids are, for example, acids Hydracids, such as hydrochloric acid, sulfuric acid, or acid phosphoric. Suitable organic acids are, for example, acids carboxylic, phosphonic, sulfonic or sulfamic, for example acid acetic acid, propionic acid, octanoic acid, decanoic acid, acid dodecanoic acid, glycolic acid, lactic acid, acid 2-hydroxybutyric acid, gluconic acid, acid glucose monocarboxylic acid, fumaric acid, succinic acid, acid adipic acid, pimelic acid, subic acid, azelaic acid, acid Malic acid, tartaric acid, citric acid, glucaric acid, acid galactaric, amino acids, such as glutamic acid, acid aspartic, N-methylglycine, acetylaminoacetic acid, N-acetylasparragine, or N-acetylcysteine, pyruvic acid, acid acetoacetic acid, phosphoserine, acid 2 or 3-glycerophosphoric, maleic acid, acid hydroximaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, benzoic acid, salicylic acid, 1st acid 3-hydroxynaphthyl-2-carboxylic acid, 3,4,5-Trimethoxybenzoic acid, acid 2-phenoxybenzoic acid 2-acetoxybenzoic acid 4-aminosalicylic, phthalic acid, acid phenylacetic, glucuronic acid, galacturonic acid, methane acid or ethane sulfonic acid 2-hydroxyethanesulfonic acid ethane-1,2-disulfonic acid benzenesulfonic acid, 2-naphthalenesulfonic acid, acid 1,5-naphthalene disulfonic acid N-cyclohexylsulfamic acid N-methyl, N-ethyl or N-propyl sulfamic acid, or other acids Organic protons, such as ascorbic acid. When they are present acid groups (for example carboxyl), may be present the corresponding salts with the bases or salts suitable cationic, such as non-toxic metal salts of the groups Ia, Ib, IIa or IIb of the periodic table of the elements, especially suitable alkali metal salts, such as lithium, sodium or potassium, or alkaline earth metal salts, such as calcium or magnesium salts, or zinc or ammonium salts, or also salts with organic amines, such as mono, di or unsubstituted or substituted trialkylamines, especially mono, di or tri-lower alkylamines, or with compounds quaternary ammonium, for example with N-methyl-N-ethylamine, diethylamine, triethylamine, mono, bis or tris (2-hydroxy-alkyl lower) amines, such as mono, bis or tris (2-hydroxyethyl) amine, N, N-dialkyl lower-N- (hydroxy-alkyl lower) amines, such as N, N-dimethyl-N- (2-hydroxyethyl) -amine or tri- (2-hydroxyethyl) -amine, or N-methyl-D-glucamine, or quaternary ammonium salts, such as salts of tetrabutylammonium

For isolation or purification purposes also it is possible to use pharmaceutically unacceptable salts, for example picratos and perchlorates. Only pharmaceutically salts acceptable or free compounds not present as salt (optionally in the form of pharmaceutical preparations) reach therapeutic use, and therefore these are preferred.

In view of the close relationship between novel compounds in free form and in the form of their salts, including salts that can be used as products intermediates, for example in the purification or identification of novel compounds, any reference to free compounds, previously made in this document and hereafter in this document, it should be understood as also refers to the corresponding salts, as appropriate and convenient.

The compounds of formula I have valuable pharmacological properties. In particular, they show specific inhibitory activities that are of high interest pharmacological. They are preferably active as inhibitors of tyrosine kinase and / or also as serine / threonine inhibitors protein kinases For example, they show very inhibitory actions good against the tyrosine activity of the factor receptor epidermal growth (EGF) and the factor receptor vascular endothelial growth (VEGF). In addition, they show efficacy against a number of other tyrosine protein kinases, such as c-erbB2 kinase. The effects mediated by such specific enzyme activities play a key role in the signal transmission in a large number of mammalian cells, including human cells, especially epithelial cells, immune system cells and nervous system cells central and peripheral. For example, tyrosine activation protein kinase associated with receptor receptor for factor EGF epidermal growth (EGF-R-TPK) is a prerequisite for cell division and therefore for the proliferation of a given cell population. Therefore, an increase in concentration of the specific protein tyrosine kinase inhibitors of EGF receptor inhibits cell proliferation. Similarly, an inhibition of tyrosine protein kinase activity of the VEGF vascular endothelial growth factor (VEGF-R-TPK, for example KDR and Flt-1) achieves a reduction in vessel formation and therefore, can contribute to the prevention of the growth of tumors that depend on a sufficient blood supply, as well as the prevention of metastasis formation. A comparable effect It also applies to other kinases mentioned earlier in the this document and hereafter in this document, and analogous to them.

In addition to or instead of inhibition of tyrosine protein kinase of the EGF receptor and / or the kinase of the VEGF receptor, the compounds of the formula I inhibit, in different grades, other tyrosine protein kinases that are involved in the transmission of signals mediated by factors trophic, for example abl kinase, especially v-abl kinase, src family kinases kinases, especially c-src kinase, lck, fyn; other kinases of the EGF erb family, for example c-erbB2 kinase (HER-2), c-erbB3 kinase, c-erbB4 kinase; members of the receptor tyrosine protein kinase family of PDGF, for example PDGF receptor kinase, receptor kinase of CSF-1, Kit receptor kinase and FGF receptor; growth factor receptor kinase insulin-like (IGF-1 kinase), and / or serine / threonine kinases, for example protein kinase C or cdc kinases, all of which play a role in the regulation of growth and transformation in mammalian cells, including human cells

Inhibition of the EGF receptor specific tyrosine protein kinase (EGF-R-TPK) can be demonstrated using known methods, for example using the recombinant intracellular domain of the EGF receptor [EGF-R ICD; see for example E. McGlynn et al ., Europ. J. Biochem. 207, 265-275 (1992)]. In comparison to the control without inhibitor, the compounds of formula I inhibit the enzymatic activity by 50% (IC 50), for example in a concentration of from 0.001 to 100 µM, especially from 0.001 to 20 µM.

The above-mentioned inhibition of v-abl tyrosine kinase is determined by the methods of N. Lydon et al ., Oncogene Research 5, 161-173 (1990) and JF Geissler et al ., Cancer Research 52, 4492-4498 (1992) . In these methods, [Val 5] - angiotensin II and [γ-32 P] -ATP are used as substrates.

Inhibition of c-erbB2 tyrosine kinase (HER-2) can be determined, for example, in the same manner as for EGF-R-TPK (see House et al ., Europ. J. Biochem. 140, 363-367 [1984]). The c-erbB2 kinase can be isolated, and its activity determined, by protocols known per se, for example according to T. Akiyama et al ., Science 232, 1644 (1986).

The activity of the compounds of formula I on EGF-stimulated tyrosine cell phosphorylation at the EGF receptor in the human A431 epithelial cell line can be determined by an ELISA (EGFR-ELISA) described in U. Trinks et al. ., J. Med. Chem. 37: 7, 1015-1027 (1994).

Stimulation of resting cells of BALB / c3T3 by EGF rapidly induces the expression of c-fos nrns ("nRNS" - "non reactive nitrogen species" - non-nitrogen reactive species). By pretreating the cells with a compound of formula I before stimulation with EGF, c-fos expression can be inhibited. This test procedure is described in the same way in U. Trinks et al ., J. Med. Chem. 37: 7, 1015-1027 (1994).

Other tests may be carried out for determination of the inhibitory action against additional kinases, for example those mentioned above, such as Kit, Flt-1 or also KDR, using tyrosine kinase respective, which can be used as the fusion protein glutathione-S-transferase using, for example, a baculovirus system. Fusion proteins respective are purified by chromatography using a glutathione-sepharose column, and are used to determine the IC 50 values of the test compounds of formula I. With Flt-1 or KDR, it could be found IC 50 values in the range of 1 nM to 200 µM, per example with KDR in the range of 100 nM to 100 µM.

In the micromolar range, for example, the compounds of formula I also similarly show an inhibition of cell growth of EGF-dependent cell lines, such as the BALB / c mouse keratinocyte epidermoid cell line (see Weissmann, BA, and Aaronson, SA, Cell 32, 599 (1983)) or the A431 cell line, which are recognized as useful conventional sources of EGF-dependent epithelial cells (see Carpenter, G., and Zendegni, J. Anal. Biochem. 153, 279 -282 (1985)). In a known test method [see Meyer et al ., Int. J. Cancer 43, 851 (1989)], the inhibitory action of the compounds of formula I is determined shortly as follows: BALB / MK cells are transferred ( 10,000 / well of the microtiter plate) to 96-well microtiter plates. Test compounds (dissolved in DMSO) are added in a series of concentrations (dilution series), so that the final concentration of DMSO does not exceed 1% (v / v). After the addition, the palcas are incubated for three days, during which time the control cultures without the test substance can undergo at least three cycles of cell division. The growth of MK cells is measured by staining with methylene blue: After incubation, the cells are fixed with glutaraldehyde, washed with water and stained with 0.05% methylene blue. After a washing step, the dye is eluted with 3% HCl and the optical density per well of the microtiter plate at 665 nm is measured using a multiscan Titertek. IC 50 values are determined by a computer-assisted system using the formula:

IC_ {50} = [(DO_ {test} - DO_ {start}) / (DO_ {control} - DO_ {start})] \ x \ 100

The IC50 value in those experiments is given like that concentration of the test compound in question that gives as a result a cell count that is 50% lower than obtained using the control without inhibitor.

The compounds of formula I can also achieve the inhibition of tumor cell growth in vivo , as shown, for example, by the test described below: the test is based on the inhibition of the growth of human epidermoid carcinoma A431 (ATCC No. CRL 1555; American Type Culture Collection, Rockville, Maryland, USA; see Santon, JB, et al ., Cancer Research 46, 4701-4705 (1986) and Ozawa, S., et al ., Int. J Cancer 40, 706-710 (1987)), which is transplanted into BALB / c female nude mice (Bomholtgard, Denmark). This carcinoma shows a growth that correlates with the degree of expression of the EGF receptor. In the experiment, tumors having a volume of approximately 1 cm 3 cultured in vivo from experimental animals under sterile conditions are surgically removed. The tumors are crushed and suspended in 10 volumes (w / v) phosphate buffered saline. The suspension is injected subcutaneously ("sc") (0.2 ml / mouse in phosphate buffered saline) in the left side of the animals. Alternatively, 1 x 10 6 cells of an in vitro culture can be injected in 0.2 ml of phosphate buffered saline. Treatment is started with the test compounds of formula I 5 or 7 days after transplantation, when the tumors have reached a diameter of 4-5 mm. Each respective active substance (in different doses for different groups of animals) is administered once daily for 15 successive days. Tumor growth is determined by measuring the diameter of the tumors along two axes that are perpendicular to each other. Tumor volumes are calculated using the known formula px L x D 2/6 (see Evans, BD, et al , Brit. J. Cancer 45, 466-8 (1982)). The results are given as treatment / control percentages (T / C x 100 = T / C%).

Alternatively to the A431 cell line, other cell lines can also be used to demonstrate the antitumor activity of the compounds of formula I in vivo , for example:

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the MCF-7 breast adenocarcinoma cell line (ATCC No. HTB 22; see also J. Natl. Cancer Inst. (Bethesda) 51, 1409-16 [1973]);

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the MDA-MB 468 breast adenocarcinoma cell line (ATCC No. HTB 132; see also In Vitro 14, 911-15 [1978]);

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the MDA-MB 231 breast adenocarcinoma cell line (ATCC No. HTB 26; see also J. Natl. Cancer Inst. (Bethesda) 53, 661-74 (1974));

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the Colo 205 colon carcinoma cell line (ATCC No. CCL 222; see also Cancer Res. 38, 1345-55 [1978]);

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the HCT 116 colon carcinoma cell line (ATCC No. CCL 247; see also Cancer Res. 41, 1751-6 [1981]);

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the DU145 prostate carcinoma cell line (ATCC No. HTB 81; see also Cancer Res. 37, 4049-58 [1978]); Y

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the PC-3 prostate carcinoma cell line (ATCC No. CRL 1435; see also Cancer Res. 40, 524-34 [1980]).

The efficacy of the compounds of formula I of the invention as inhibitors of tyrosine kinase activity of VEGF receiver can be demonstrated as follows:

test to determine the activity against tyrosine kinase of the VEGF receptor. The test is carried out using the Flt-1 tyrosine kinase of the VEGF receptor. The detailed procedure is as follows: 30 µl of kinase solution (10 ng of Flt-1 kinase domain, Shibuya et al ., Oncogene 5, 519-24 [1990]) are incubated together in Tris • HCl 20 mM pH 7.6, 3 mM manganese dichloride (MnCl 2), 3 mM magnesium chloride (MgCl 2) and poly (Glu, Tyr) 4: 1 3 µg / ml (Sigma, Buchs, Switzerland ), [33 P] -ATP 8 µM (0.2 µCi / lot), 1% dimethylsulfoxide, and 0 to 50 µM of the compound to be tested for 15 minutes at room temperature. Then, the reaction is terminated by adding 10 µL of 0.25 M ethylenediamine tetraacetate (EDTA), pH 7. Using a "Multichannel Dispenser" (LAB SYSTEMS, USA), a 20 µl aliquot to a PVDF membrane - (= polyvinyl difluoride) - Immobilon P (Millipore, USA), which is then incorporated into a Millipore microtiter filter manifold ("Millipore microtiter filter manifold" ), and is connected in vacuo.After completely removing the solvent, the membrane is incubated four times in a row in a bath containing 0.5% phosphoric acid (H3PO4), each time for 10 minutes at After stirring, it is then transferred to a Hewlett Packard Topcount collector ("Hewlett Packard TopCount Manifold"), and the radioactivity is measured after adding 10 µl of Microscint® (β-scintillation counter liquid; Packard USA). ) The IC 50 values were determined by linear regression analysis of the percentages for the inhi bition of each test compound in three concentrations (as a rule 0.01, 0.1 and 1 µM). Preferably, inhibitory concentrations (IC 50 with 50% maximum inhibition are found compared to a control without the inhibitory substance of formula I) in the range of 1 to 300 µM, especially in the range of 1 to 100 µM .

Here, the activity in vivo of a compound of formula I can also be demonstrated using the test described above with A-431 cells or other cell lines in mice.

The inhibition of VEGF-induced KDR receptor autophosphorylation can be confirmed with an additional in vitro experiment in cells: transfected CHO cells, which permanently express the KDR of the human VEGF receptor, are planted in culture medium (with fetal calf serum at 10% = FCS) in 6-well cell culture plates and incubate at 37 ° C, 5% CO2 until they show a confluence of approximately 80%. The compounds to be tested are then diluted in culture medium (without FCS, with 0.1% bovine serum albumin) and added to the cells (controls only comprise medium without test compounds). After incubating for 2 hours at 37 ° C, the recombinant VEGF is added; The final concentration of VEGF resulting is 20 ng / ml. After incubating for an additional five minutes at 37 ° C, the cells are washed twice with ice cold PBS (phosphate buffered physiological saline) and immediately lysed in 100 µl of lysis buffer per batch. The lysates are then centrifuged to extract cell nuclei, and protein concentrations of the supernatants are determined using a commercial protein assay (BIORAD). Then the lysates can either be used immediately or, if necessary, stored at -20 ° C.

A sandwich ELISA is carried out to measure phosphorylation of the KDR receptor. An antibody is adsorbed KDR-specific monoclonal (for example, Mab 1495.12.14; prepared by H. Towbin) on black ELISA plates (Optiplate ™) Packard HTRF-96). Then they wash the plates and free protein binding sites that remain with a 1% bovine serum albumin in PBS. Then cell lysates (20 µg of protein / lot) are incubated overnight at 4 ° C with an alkaline phosphatase-linked antiphosphotyrosine antibody (PY20: AP of Transduction Laboratories). Then the antiphosphotyrosine antibody binding using an AP substrate luminescent (CDP-Star, ready to use, with Emerald II; TROPIX). Luminescence is measured in a scintillation counter in microplate Top Count Packard (Top Count). The difference between the positive control signal (stimulated with VEGF) and control signal negative (not stimulated with VEGF) corresponds to phosphorylation of the KDR receptor induced by VEGF (= 100%). Activity is calculated of a test compound as% inhibition of VEGF-induced KDR receptor phosphorylation, according to which the concentration of the compound that induces half of the inhibition maximum is defined as ED50 (effective dose for 50% of inhibition).

The suitability of a compound of formula I for arthritis treatment, as an example of a disease rheumatoid or rheumatic inflammatory, can be tested as follow:

The well-known model of adjuvant arthritis in rats (adjuvant arthritis model in rats; "Rat adjuvant Arthritis Model"; Pearson, Proc. Soc. Exp. Biol. 91, 95-101 (1956)) is used to demonstrate anti- activity arthritic of a compound of formula I. Individual Wistar rats (5 animals per group, weight of about 200 g, acquired from Iffa Credo, France) are injected intradermally ("id") through the tail with 0 , 1 ml of mineral oil containing 0.6 mg of Mycobacterium tuberculosis inactivated by lyophilized heat. Rats are treated with a test compound (3, 10 or 30 mg / kg orally once a day) or with the vehicle (water) from day 15 to day 22 (therapeutic dose schedule). At the end of the experiment, the inflammation of the tarsal joints is measured by a small king's foot ("micro-sliding gauge"). The percentage of each paw inflammation inhibition is calculated by comparing the value of arthritic animals treated with the vehicle (0% inhibition) and with healthy animals treated with the vehicle (100% inhibition).

The effect of a compound of formula I on pain in the following model of noci-reception. In the model, the hyperalgesia, produced by an intraplantar injection of yeasts, using increasing pressure on the foot until the test animal shouts or removes the leg of the pressure pad that It is being applied. The model reacts to COX inhibitors, and diclofenac (3 mg / kg) is used as a positive control.

The initial pressure is determined individually that is needed to induce a vocal sound or the withdrawal of the leg (2 hours before treatment) in male rats Sprague-Dawley (weight of about 180 g, acquired from Iffa Credo, France). Then, 100 µl of one is injected 20% yeast suspension in water on the hind legs. At 2 hours of this, the rats are treated by oral administration with the test compound (3, 10 or 30 mg / kg) or with diclofenac (3 mg / kg) or with the vehicle (physiological saline) orally (time point: zero), and pressure test 1 and 2 was repeated hours after administration. Using the device Conventional (Ugo Basile, Italy), the pressure required to measure induce a vocal expression or the withdrawal of the paw in these time points in animals treated with the test compound, and it is compared to those treated only with the vehicle.

As a result of its properties previously mentioned, for example as tyrosine kinase inhibitors of VEGF or EGF receptor, the compounds of formula I are especially suitable for treating rheumatoid diseases or rheumatic inflammatory, particularly its manifestation in the locomotor system, for example rheumatoid diseases inflammatory such as polyarthritis, and / or for the treatment of pain.

Starting from its effectiveness as inhibitors of VEGF receptor kinase activity, the compounds of formula I they inhibit in particular the growth of blood vessels, and are by both effective, for example, against a number of diseases associated with an angiogenesis deregulation, especially diseases caused by ocular neovascularization, such as diabetic retinopathy or macular degeneration induced by age; psoriasis, hemangioblastoma, such as hemangioma; diseases proliferative mesangial cells, such as diseases acute or chronic renal, for example, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathic syndrome, transplant rejection, or especially kidney disease inflammatory, such as glomerulonephritis, especially mesangioproliferative glomerulonephritis, uremic syndrome hemolytic, diabetic nephropathy or hypertensive nephrosclerosis; atheroma, arterial restenosis, autoimmune diseases, acute inflammation, fibrotic diseases (for example cirrhosis of the liver), diabetes, endometriosis, chronic asthma, atherosclerosis arterial or post-transplant diseases neurodegenerative and in particular neoplastic diseases (solid tumors, and also leukemia and other tumors "liquids", especially those that express c-kit, KDR or flt-1), such as, in particular breast cancer colon cancer lung cancer (especially small cell lung cancer), cancer of prostate, Kaposi's sarcoma, CNS tumors, ovarian cancer, renal tumors or tumors associated with VHL. A compound of formula I inhibits the growth of tumors and is especially suitable for prevention of metastatic tumor expansion and growth of micrometastases.

Due to its effectiveness as inhibitors of receptor tyrosine kinase activity for growth factor  epidermal (EGF) or other tyrosine protein kinases mentioned, the compounds of formula I are especially useful in the treatment of benign or malignant tumors. They can achieve a tumor regression and avoid the formation of tumor metastases and The growth of micrometastases. They can be used especially in the case of epidermal hyperproliferation (psoriasis), in the treatment of epithelial neoplasms, for example breast carcinomas, and in leukemia. In addition, the compounds of formula I to treat system diseases immunological, as long as several or preferably a single tyrosine protein kinase (s) and / or (in addition) serine / threonine protein kinase (s); also can the compounds of formula I be used in the treatment of disorders of the central or peripheral nervous system in which you are involved the transmission of signals by several or, preferably, a single tyrosine protein kinase (s) and / or (in addition) serine / threonine protein kinase (s).

In general, the present invention relates to also to the use of the compounds of formula I in the inhibition of The protein kinases mentioned.

The proliferation inhibition of, for example, tumor cells or epithelial cells in the case of psoriasis, may, in certain circumstances, be based on the inhibition of one or more of the aforementioned kinases, or there may also be other additional mechanisms unknown.

The compounds according to the invention can administered alone or in combination with one or more other agents therapeutic, possible combination therapy that takes the form of fixed combinations or administration of a compound of the invention and one or more other therapeutic agents that separate or are administered independently of each other, or the combined administration of fixed combinations and one or more of Other therapeutic agents. In particular, a compound of formula I for example in the case of tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, surgical intervention, or a combination of these. It is equally long-term therapy is possible since it is an adjuvant therapy in the context of other treatment strategies, such as described above. Other possible treatments are therapies to maintain the patient's condition after regression tumor, or even chemopreventive therapy, for example in patients at risk.

Therapeutic agents for a combination possible are especially one or more cytotoxic compounds or cytostatic, antiproliferative, for example an agent chemotherapeutic or several agents selected from the group that includes, but is not limited to, a biosynthesis inhibitor of polyamine, an inhibitor of a protein kinase, especially a serine / threonine protein kinase, such as protein kinase C, or a tyrosine protein kinase, such as the tyrosine kinase of the EGF receptor, for example PKI166, the receptor tyrosine kinase of VEGF, for example PTK787, or the receptor tyrosine kinase of PDGF, for example STI571, a cytokine, a negative regulator of growth, such as TGF-? or IFN-?, An aromatase inhibitor, for example letrozole or anastrozole, an inhibitor of the interaction of a domain SH2 with a phosphorylated protein, antiestrogens, inhibitors of topoisomerase I, such as irinotecan, topoisomerase inhibitors II, active ingredients against microtubules, for example paclitaxel, discodermolide or an epothilone, alkylating agents, antineoplastic antimetabolites, such as gemcitabine or capecitabine, platinum compounds, such as carboplatin or cisplatin, anti-angiogenic compounds, agonists of gonadorelin, antiandrogens, bisphosphonates, for example, AREDIA®  or ZOMETA®, and trastuzumab. The structure of active ingredients identified by code numbers, generic names or commercials can be taken from the current edition of the compendium standard "The Merck Index" or databases, for example, International Patents (for example, IMS World Publications). He corresponding content thereof is incorporated herein document as reference.

Preferred embodiments of the invention

In the following preferred embodiments of the invention, general definitions can be substituted, independently of each other, by the definitions Preferred mentioned above or below, as which embodiments resulting from the invention are the preferred.

Preference is given to a compound of formula I, in which X means either nitrogen or a carbon atom which carries a radical A; A means hydrogen or -COOW, in which W means alkyl or hydrogen; Y is NR ', S or O, in which R' means hydrogen or alkyl; R means alkyl, aryl, heterocyclyl, cycloalkyl, arylalkyl, heterocyclylalkyl or cycloalkylalkyl, according to which each of these radicals is not substituted or substituted; or COOR ', COR' or CONR'R '', in which R ' and R '', independently of each other, are hydrogen or alkyl, aryl, heterocyclyl, cycloalkyl, arylalkyl, heterocyclylalkyl or cycloalkylalkyl, according to which each of these radicals is unsubstituted or substituted; and Q is aryl, aryl-lower alkyl or heterocyclyl, which are, respectively, unsubstituted or substituted; as well as a salt of same.

A compound of formula I, in the one that X means either nitrogen or carbon atom that it carries a radical A; A means hydrogen or -COOW, in which W means alkyl or hydrogen; Y is NR ', S or R, according to which R' means hydrogen or alkyl; R means aryl; and Q is aryl, aryl-lower alkyl or heterocyclyl, which are respectively unsubstituted or substituted; as well as a salt of same.

The invention relates in particular to a compound of formula I, in which X means either nitrogen (preferred) or a carbon atom bearing a radical A; TO means hydrogen or -COOW, in which W means alkyl, especially lower alkyl, or hydrogen; R means aryl, and Q means aryl; or a salt thereof.

Preference is given to a compound of formula I in which X means either nitrogen or a carbon atom that it carries a radical A; A means hydrogen; R is phenyl that is substituted by nitro or amino; and Q is phenyl which is substituted by one or more radicals (especially 1 or 2 radicals), which, independently of each other, they are selected from hydroxyl, lower alkoxy, especially methoxy, and halogen, especially  chlorine or bromine; or a salt thereof.

In addition, a compound of formula I is preferred in which X means either nitrogen or a carbon atom that it carries a radical A; A means hydrogen; R means aryl; and Q means aryl, aryl-lower alkyl or heterocyclyl; or a salt thereof, according to which aryl is phenyl, naphthyl, fluorenyl or phenanthrenyl, which are respectively not substituted or substituted by up to three selected substituents of amino; lower alkylamino; N, N-di-lower alkylamino; amino lower alkyl; alkylamino lower-lower alkyl; N, N-di-alkylamino lower-lower alkyl; lower alkanoylamino; halogen, lower alkyl; lower alkenyl; phenyl; naphthyl; halogen-lower alkyl; hydroxyl; alkoxy lower; lower alkenyloxy; phenyl-alkoxy lower; lower alkanoyloxy; carbamoyl lower alkoxy; lower carboxy-alkoxy; phenyl-alkoxycarbonyl lower-lower alkoxy; mercapto; nitro; carboxyl; lower alkoxycarbonyl; phenyl-lower alkoxycarbonyl; cyano; alkoxy C 8 -C 12; carbamoyl; alkylcarbamoyl lower; N, N-di-alkylcarbamoyl lower; N-monkey or N, N-diphenyl-alkyl-carbamoyl  lower; lower alkanoyl; phenyloxy; halogen-lower alkyloxy; alkoxycarbonyl lower; lower alkylpiperazinylcarbonyl; morpholinylcarbonyl; lower alkylpiperazinyl-lower alkyl; lower morpholinyl alkyl; lower alkyl mercapto; halogen lower alkylmercapto; hydroxy lower alkyl; lower alkanesulfonyl; halogen-lower alkanesulfonyl; phenylsulfonyl; dihydroxyboro; lower alkylpyrimidinyl; oxazolyl; lower alkyldioxolanyl; pyrazolyl; lower alkylpyrazolyl; lower alkylenedioxy attached to two adjacent carbon atoms; pyridyl; piperazinyl; lower alkylpiperazinyl; morpholinyl; phenylamino or phenyl-lower alkylamino or not substituted or substituted on the phenyl moiety by halogen, lower alkyl, hydroxyl, lower alkanoyloxy, alkoxy lower, carboxyl, lower alkoxycarbonyl, carbamoyl, N- lower alkylcarbamoyl, N, N-di-lower alkylcarbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N, N-di-lower alkylamino or trifluoromethyl; or a radical of formula R 3 -S (O) m -, in which R 3 it is lower alkyl and m is 0, 1 or 2.

Special preference is given to a compound of formula I in which X means either nitrogen or an atom of carbon bearing a radical A; A means hydrogen; R is phenyl which is substituted by amino; especially 4-aminophenyl; and Q is phenyl which is substituted by one or more radicals, especially 1 or 2 radicals, that are independently select from each other, hydroxyl, lower alkoxy, especially methoxy, and halogen, especially chlorine or bromine.

Particular preference is given to a compound of formula I, in which X means either nitrogen or an atom of carbon bearing a radical A; in which A means hydrogen; R is phenyl which is substituted by nitro, amino, lower alkylpiperazinylcarbonyl, morpholinylcarbonyl, N, N-di-lower alkylcarbamoyl, N, N-di-alkylamino lower-lower alkyl, alkylpiperazinyl lower-lower alkyl or morpholinyl lower alkyl; and Q is benzyl, phenylethyl; phenyl that is not substituted or is substituted by one or more radicals, than independently of each other, select from hydroxyl, lower alkyl, lower alkoxy and halogen; pyridyl which is substituted by hydroxyl or alkoxy lower; or indolyl which is substituted by halogen and allyl lower, as well as a salt thereof.

A compound is also especially preferred. of formula I, in which Y is NH (imino).

A compound selected from the compounds of formula I mentioned in the examples, or a salt thereof, provided that at least one group forming a Salt.

Preparation Procedure

In the following procedures, unless indicate otherwise, the symbols R, A, Q, X and Y respectively they have the meanings mentioned for the compounds of formula I, according to which the meanings indicated as preferred in the starting materials are preferred in the same way.

Compounds of formulas I, or salts thereof, by known procedures, which, without However, they are new to these compounds, especially as which

a) a compound of formula II,

2

in which X and R have the meanings provided for a compound of formula I and L means a leaving group, for example chlorine, is reacted with an amine, a phenol or thiol of formula III,

(III) Q-YH

in which Q has the meanings provided for the compounds of formula I and Y is NR ', S or O, according to which R 'means hydrogen or alkyl; in which, if it is necessary, the functional groups present in a compound of formula II and / or III, which should not take part in the reaction, are present in protected form, and the protective groups that are present is separate

and, if desired, a compound of formula I that can be obtained it becomes a different compound of formula I;  a compound of free formula I that can be obtained becomes a salt; a salt that can be obtained from a compound of formula I it becomes another salt or the free compound of formula I; I isomeric mixtures that can be obtained from compounds of formula I are separated into individual isomers;

Detailed description of the procedure

A compound of formula II or III may be present in free form, or if the reaction of groups is to be avoided functionalities that should not participate in the reaction, in a way which the functional ones that do not participate are protected.

If in a compound of formula II has (n) of or one or more functional groups need to be protected, by for example, hydroxyl, carboxyl, amino or mercapto, etc., because no they must take part in the reaction, the protective groups are the ones that they are normally used in the synthesis of peptide compounds, and also of cephalosporins and penicillins, as well as derivatives of nucleic acids and sugars. These protecting groups may be already present in the precursors and should protect the groups functional in question against side reactions not desired, such as acylations, etherifications, esterifications, oxidations, solvolysis, and similar reactions. The groups protectors for functional groups in starting materials whose transformation should be avoided, especially include conventional protecting groups that are normally used in the synthesis of peptide compounds, cephalosporins, penicillins or derivatives of nucleic acids and sugars. In certain cases, protective groups can achieve, in addition to this protection, a course of selective reactions, for example stereoselective. Is a characteristic of the protective groups that they themselves lend easily, that is to say without unwanted side reactions, upon elimination, usually by solvolysis, reduction, photolysis or also by enzymatic activity, for example in conditions analogous to physiological conditions, and that are not present in the final products.

One skilled in the art knows, or can easily establish, which protecting groups are suitable for  reactions mentioned earlier in this document and in the following in this document. The protection of the groups functional by such protecting groups, the groups protectors themselves, and their separation reactions are describe, for example, in conventional reference works, such as J.F.W. McOmie, "Protective Groups in Organic Chemistry ", Plenum Press, London and New York 1991, in T.W. Greene, P.G.M. Wuts, "Protective Groups in Organic Synthesis", 2nd edition, John Wiley & Son Inc., 1981, in "The Peptides "; volume 3 (: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, in "Methoden der organischen Chemie "(Organic chemistry methods), Houben Weyl, 4th edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, "Aminosäuren, Peptide, Proteine" (Amino Acids, peptides, proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and in Mochen Lehmann, "Chemie der Kohlenhydrate: Monosac charide und Derivate ", (Chemistry of hydrates carbon: monosaccharides and derivatives) Georg Thieme Verlag, Stuttgart 1974

A leaving group in a compound of formula II it is preferably halogen, especially bromine, or mainly chlorine or iodine Other outgoing groups are possible, for example, aryl- or alkyl-sulfonyl groups, for example 4-toluenesulfonyl.

The reaction between the compound of formula II and an amine of formula III (Y = NR ') preferably takes place in a suitable polar solvent, especially in an alcohol, especially a lower alkanol, such as methanol, propanol, isopropanol or in particular ethanol or n-butanol, or mixtures thereof, or in a fusion without the addition of solvents, especially if one of the reagents is present in liquid form; at elevated temperature, preferably between 60 ° C and the reflux temperature of the reaction mixture relevant, for example at reflux, or at a temperature between approximately 70 and 120 ° C. The compound of formula III also it may be present as salt, for example an addition salt of acid with a strong acid, such as a hydrogen halide, by example the hydrogen chloride salt, or the acid can be added relevant to the reaction mixture, for example in the presence of a suitable solvent, such as an ether, for example, dioxane. Yes L it is iodine, the reaction is preferably carried out in a inert solvent, such as toluene, in the presence of a base, especially an alkali metal carbonate, such as carbonate of dipotassium, in the presence of catalytic amounts of a complex of appropriate noble metal catalyst, such as tetrakis- (triphenylphosphine) -palladium, at a high temperature, especially between 80 and 115 ° C.

The reaction between the compound of formula II and a phenol of formula III (Y = O) preferably takes place in presence of copper salts instead of with the conditions of the Ullmann ether synthesis, as described in Russ. Chem Rev. 43, 679-689 (1974). In some cases, the reaction can be carried out by heating the compounds of formula II and formula III (Y = O) in the presence of a base, such as carbonate of potassium, in a suitable solvent, for example dimethylformamide

The reaction between the compound of formula II and a thiol of formula III (Y = S) preferably takes place from known manner in a polar solvent, such as dimethylformamide, dimethylsulfoxide or HMPT, if necessary in the presence of a appropriate catalyst, such as palladium complex tetrakis- (triphenylphosphine) -palladium (O).

Reactions

In the additional procedural steps, carried out as desired, the functional groups of the starting compounds that should not take part in the reaction can be present unprotected or may be protected by example by one or more of the mentioned protecting groups earlier in this document in procedure a). Then the protecting groups are totally or partially removed according to one of the methods described in procedure a).

Compounds of formula can be reacted I, in which the nitro group is present as a substituent in an aryl radical, by hydrogenation to give the compound corresponding, in which an amino group is present instead from the nitro group. In this case the hydrogenation is carried out well with elemental hydrogen (H2) in the presence of a catalyst suitable, for example a Raney catalyst, such as nickel from Raney or Raney cobalt, in a solvent or solvent mixture suitable such as an ether, for example tetrahydrofuran, and / or a di-lower alkyl-imidazolidinone, such as 1,3-dimethyl-2-imidazolidinone  (DMEU), preferably at temperatures between 0 and 50 ° C, for example, at room temperature, according to which the pressure can rise or fall, preferably at normal pressure; or with nascent hydrogen, for example produced by the reaction of a tin (II) salt, such as tin (II) chloride, in a appropriate solvent, such as an alcohol, for example ethanol, propanol or butanol, at preferred temperatures between 10 ° C and the reflux temperature of the reaction mixture, preferably at temperatures between room temperature and 80 ° C.

Salts of a compound of formula I with a salt forming group in a known manner of in herself. Thus, acid addition salts of compounds of formula I for example by treatment with a acid or a suitable anion exchange reagent, and salts with cations, for example by treatment with a metal salt, a base or a cation exchanger. Normally, the salts they can become free compounds, for example in the case of acid addition salts by treatment with an agent suitable basic, for example with carbonates, hydrogen carbonates, or alkali metal hydroxides, for example potassium carbonate or sodium hydroxide, or in the case of salts, with bases.

Steroisomeric mixtures, for example, mixtures of diastereoisomers, can be separated into their corresponding isomers in a manner known per se by appropriate separation methods. Mixes diastereoisomers can be separated into their diastereoisomers individual by fractional crystallization, chromatography, solvent distribution, and procedures Similar. This separation can take place well in the phase of one of the starting compounds or in a compound of formula I proper. The enantiomers can be separated through the formation of diastereoisomeric salts, for example with an acid enantiomerically pure chiral, or by chromatography, by HPLC example, using chromatographic substrates with ligands chiral

The compounds of formula I, in which R is a group phenyl-C (= O) -O-alkyl lower, especially a group phenyl-C (= O) -O-methyl, they can become compounds of formula I, in which R is a group phenyl-C (= O) -O-H, for example by hydrolysis in the presence of an appropriate base, for example LiOH, if necessary in the presence of a solvent appropriate, for example, dioxane. This free acid of formula I can serve as an educate for the preparation of other derivatives, especially carboxylic acid esters and acid amides carboxylic, using procedures known in the bibliography. A carboxylic acid amide of this type, ie a compound of formula I, in which R is a group phenyl-C (= O) -NR'R '', can converted by a known form into a compound of formula I, in which R is a group phenyl-CH2 -NR'R '', by means of a reaction with an appropriate reducing agent, for example hydride of diisobutylaluminum in tetrahydrofuran.

General procedure conditions

All the process steps described herein can be carried out under known reaction conditions, preferably those specifically mentioned, in the absence of or normally in the presence of solvents or diluents, preferably those that are inert to the reagents used and which can dissolve them, in the absence or presence of catalysts, condensing agents or neutralizing agents, for example ion exchangers, normally cation exchangers, for example in the form of H +, depending on the type of reaction and / or reagents at a reduced, normal temperature or elevated, for example in the range of from -100 ° C to about 190 ° C, preferably from about -80 ° C to about 150 ° C, for example at -80 to 60 ° C, at room temperature, from -20 to 40 ° C or to the boiling point of solvent used, at atmospheric pressure or in a closed container, if it needs to be under pressure, and / or in an atm inert atmosphere, for example of argon or
nitrogen.

Salts may be present in all starting compounds and their intermediates, if these They contain salt forming groups. The salts can also be present during the reaction of such compounds, provided that no The reaction is thus disturbed.

In all reaction phases, mixtures Isomers that occur can be separated into their isomers individual, for example diastereoisomers or enantiomers, or in any mixture of isomers, for example racemates or mixtures diastereoisomerics, usually as described in "stages of additional procedures. "

In certain cases, usually in the reactions of dehydrogenation or aldol, it is possible to get reactions stereoselective, allowing, for example, one more recovery Easy of individual isomers.

The solvents from which they can be selected those that are suitable for the reaction in question include, for example, water, esters, usually lower alkanoate of lower alkyl, for example diethyl acetate, ethers, normally aliphatic ethers, for example diethyl ether, or ethers cyclic, for example tetrahydrofuran, aromatic hydrocarbons liquids, usually benzene or toluene, alcohols, normally methanol, ethanol or 1- or 2-propanol, nitriles, normally acetonitrile, halogenated hydrocarbons, normally dichloromethane, acid amides, usually dimethylformamide, bases, usually heterocyclic nitrogen bases, for example, pyridine, carboxylic acids, usually alkanocarboxylic acids lower, for example acetic acid, acid anhydrides carboxylic, usually lower alkane acid anhydrides, by example, acetic anhydride, cyclic, linear or hydrocarbons branched, usually cyclohexane, hexane, or isopentane, or mixtures of these solvents, for example, aqueous solutions, to unless otherwise indicated in the description of the process. Such solvent mixtures can also be used. in the final treatment, for example by chromatography or partition.

The invention also relates to the embodiments of the process in which part of a compound that can be obtained at any stage as an intermediate product and the missing steps are carried out, or the process is interrupted at any stage, or is formed a starting material under the reaction conditions, or said starting material is used in the form of a derivative or a reactive salt, or a compound is produced which can be obtained by the process according to the invention under those process conditions, and further treats said compound in situ . In the preferred embodiment, starting materials are used which lead to the compounds described hereinbefore as preferred, particularly as especially preferred, mainly preferred, and / or especially preferred.

In the preferred embodiment, a compound of formula I according to the procedures and steps of procedure defined in the examples.

The compounds of formula I, including its salts, in the form of hydrates, or its crystals may include, for example, the solvent used for crystallization (present as solvates).

Pharmaceutical preparations, methods and uses

The present invention also relates to Pharmaceutical preparations containing a compound of formula I as active ingredient and that can be used especially in the treatment of diseases mentioned at the beginning. They prefer especially preparations for enteric administration, such as nasal, oral, rectal or, especially, orally, and for parenteral administration, such as administration intravenously, intramuscularly or subcutaneous, to warm-blooded animals, especially beings humans. The preparations contain the active substance alone or, preferably, together with a pharmaceutically acceptable carrier. The dose of active substance depends on the disease that is going to be treated and of the species, its age, weight, and individual condition, individual pharmacokinetic data and the mode of administration.

The invention also relates to preparations pharmaceuticals to use in a method for treatment prophylactic or especially therapeutic of the human or animal body, especially against one of the diseases previously mentioned, to a procedure for preparing them (especially in the form of compositions for the treatment of tumors) and to a method to treat diseases previously mentioned, mainly tumor diseases, especially those mentioned above.

The invention also relates to procedures. and to the use of compounds of the formula I for the preparation of Pharmaceutical preparations containing compounds of formula I as active component (active principle).

Preference is given to a pharmaceutical composition which is suitable for administration to a blood animal hot, especially a human being or a commercially mammal useful, suffering from a disease that responds to the inhibition of tyrosine- or also serine / threonine protein kinase, for example psoriasis or especially a tumor disease, which comprises a corresponding effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof when present salt forming groups, along with at least one vehicle pharmaceutically acceptable.

In the same way a composition is preferred pharmaceutical for prophylactic treatment or in particular therapeutic of a disease that responds to the inhibition of tyrosine- or also serine / threonine protein kinase, especially tumor diseases and other diseases proliferative warm-blooded animals, especially beings humans, or a commercially useful mammal that requires a treatment of this type, especially one that suffers from disease of this type, which contains a new compound of formula I, or a pharmaceutically acceptable salt thereof, as a active ingredient in an amount that is effective so prophylactic or especially therapeutic against these diseases.

Pharmaceutical preparations containing from approximately 0.000001% up to 95% of the active substance, according to which the single dose administration forms have, preferably, from about 0.00001% to 90% and multiple dose administration forms have, preferably, from about 0.0001% to 0.5% in the case of preparations for parenteral administration or from 1% to 20% of active substance in the case of preparations for enteric administration. Dosage forms unitary are, for example, coated or uncoated tablets, ampoules, vials, suppositories or capsules. Dosage forms Additional are, for example, ointments, aerosols, etc. Examples are capsules containing from about 0.0002 g to approximately 1.0 g of active substance.

The pharmaceutical preparations of the present invention are prepared in a manner known per se, for example, by conventional mixing, granulation, coating, dissolving or freeze-drying process.
tion.

Preference is given to the use of solutions of active substance, and also suspensions or dispersions, especially aqueous solutions, dispersions or suspensions isotonic that, for example, in the case of preparations lyophilized containing the active substance alone or together with a vehicle, for example, mannitol, can be manufactured before its use.

Pharmaceutical compositions can be obtained. for oral administration, for example, by combination of the active substance with one or more solid vehicles, if if necessary by granulating a resulting mixture, and treatment of the mixture or granules, if desired, to form tablets or tablet cores, if necessary by the inclusion of additional excipients.

Suitable vehicles are especially fillers, such as sugars, cellulose preparations
and / or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starches, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolid-
na, and / or, if desired, disintegrating agents, such as the aforementioned starches, in addition to
carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof, such as alginate
sodium.

The pharmaceutical compositions that can administered orally also include hard capsules consisting of gelatin, and also sealed soft capsules consisting of gelatin and a plasticizer, such as glycerol or sorbitol. Hard capsules may contain the active substance in the form of granules, for example, in addition to fillers, such as corn starch, binders, and / or sliding agents, such as talc or magnesium stearate, and if necessary stabilizers In soft capsules, the active substance is preferably dissolved or suspended in liquid excipients suitable, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene propylene glycol, to which stabilizers can also be added and detergents

Appropriate pharmaceutical preparations that can administered rectally are, for example, suppositories that they consist of a combination of an active substance and a suppository base. Suitable suppository bases are, by for example, natural or synthetic triglycerides, hydrocarbons of paraffin, polyethylene glycols or higher alkanols.

The right formulations for parenteral administration are mainly solutions aqueous [for example in physiological saline, which can Obtained by dissolving solutions in polyethylene glycol, such as polyethylene glycol (PEG) 300 or PEG 400] from the beginning active in a water soluble form, for example a salt soluble in water, or injectable aqueous suspensions containing agents that increase viscosity, for example, sodium carboxymethyl cellulose, sorbitol and / or dextran, and when appropriate, stabilizers.

Solutions such as those used, by for example, for parenteral administration they can also used as infusion solutions.

Similarly, the invention relates to a method or method for the treatment of one of the aforementioned pathological conditions, especially a disease that responds to an inhibition of tyrosine- or also serine / threonine protein kinase, especially a corresponding tumor disease. . A compound of formula I can be administered as such or in the form of pharmaceutical compositions, prophylactically or therapeutically, preferably in an amount effective against such diseases, to a warm-blooded animal, for example a human being, which requires treatment. of this type, using the compounds especially in the form of pharmaceutical compositions. In the case of an individual having a body weight of about 70 kg the dose administered is from about 0.1 mg to about 5 g, preferably from about 0.5 mg to about 2000 mg, of a compound of the present invention Administration takes place once or several times a day, for example 1 to 3 times a day, or at intervals, preferably, for example, every 1 to 4 weeks, for example weekly, every two weeks, every three weeks or every four
weeks

The present invention also relates to particular to the use of a compound of formula I, or a salt pharmaceutically acceptable thereof, especially a compound of formula I mentioned as a preferred compound, or a salt pharmaceutically acceptable thereof, as such or in the form of a pharmaceutical formulation that contains at least one vehicle that can be used pharmaceutically, for therapeutic treatment and also prophylactic of one or more of the above diseases.

The present invention also relates to particular to the use of a compound of formula I, or a salt pharmaceutically acceptable thereof, especially a compound of formula I mentioned as a preferred compound, or a salt pharmaceutically acceptable thereof, for the preparation of a Pharmaceutical formulation for therapeutic treatment and also prophylactic of one or more of the above diseases.

The amount of dose, composition and preparation Preferred pharmaceutical formulations (medicines) that should used in each case described above.

Starting materials

The starting materials of formulas II are known, commercially available or can be produced from analogous way to known procedures, according to which if it is necessary, protective groups can also be introduced, be used and separated again at the appropriate times, analogously to the manner described above.

The starting materials of formula II can be produced by known procedures, or are known or They are commercially available.

In particular, the compounds of formula II, in the one that X means nitrogen and the remaining radicals are defined as mentioned, they can be produced by the procedure next.

By reacting a compound hydroxyaminopyrimidine of formula IV,

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3

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with a reactive derivative of a carboxylic acid of formula V,

(V) R-C (= O) -OH

in which R has the meanings given for the compounds of formula I, in an appropriate solvent or a mixture of solvents, for example in a nitrogen base tertiary, such as pyridine, preferably in the absence of oxygen, for example in an inert gas such as argon, at a high temperature, for example from 30 ° C to the temperature of reflux of the reaction mixture, especially at the temperature of Reflux.

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Thus, a compound of formula VI is obtained,

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4

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in which R have the meanings given for the compounds of formula I.

It is understood that a reactive derivative of a carboxylic acid of formula V is in particular a corresponding acid halide, for example a corresponding acid chloride of formula R- (C = O) -Cl, wherein R has the meanings given for the compounds of formula I. Such reactive carboxylic acid derivatives are known, can be produced according to or analogously to known procedures, or are commercially available.
nibles.

Then, the compound of formula VI which can be obtained in this way is reacted directly in situ or after isolation with a reagent that introduces the leaving group L, for example a compound selected from compounds having formulas VII and VIII,

(VII) P (= O) L 3

(VIII) SO2 L2

in which L has the meanings given for compounds of formula II, especially with a halide of phosphoryl such as phosphoryl chloride, or a sulfonyl halide such as sulfonyl chloride, according to which when introducing the group The leaving, instead of the hydroxyl group of the compound of formula VI, the corresponding compound of formula is obtained II.

The reaction takes place especially in a solvent or a mixture of suitable solvents, for example in a tertiary nitrogen base, such as pyridine, preferably in the absence of oxygen, for example in an inert gas such as argon, at an elevated temperature, for example 30 ° C at the temperature of reflux of the reaction mixture, especially at the temperature of Reflux.

When necessary, the functional groups in starting materials can also be protected by groups protectors, and the protecting groups that are present are Eliminate at an appropriate time. The protective groups used, its introduction and separation are described as above for the production of compounds of formula I.

The compounds of formula II, in which X is a carbon atom that carries a radical A, can be produced by The following procedure:

A β-ketoester of formula IX,

(IX) RC (= O) -CH2 -COOY

in which R has the meanings given in formula I, and Y is alkyl, especially alkyl lower, for example ethyl, is transformed with a thionyl halide such as thionyl chloride, in a compound of formula X,

(X) R-C (= O) -CH (\ simHal) -COOY

in which R and Y have the meanings given with formula IX, and Hal is halogen, especially chlorine; the reaction takes place in conditions known (see, for example, J. Heterocycl. Chem. 22, 1621-1630 (1985)).

Subsequently, the compound of formula X is reacts with an alkali metal salt of formula XI

(XI) N \ equivC-CH (Me) -A '

in which Me is an alkali metal, especially sodium, and A 'means a radical -COOW, in which W means alkyl (preferably; especially lower alkyl, such as ethyl), aryl, heterocyclyl or cycloalkyl, according to which each of these radicals is unsubstituted or substituted, in conventional conditions (see, for example, Chem. Ber. 95, 307-318 (1962)), thus producing a compound of formula XII,

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5

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in which R has the meanings given for the compounds of formula I, and A 'is defined as in the formula XI

Subsequently, the compound of formula XII is transforms, in the presence of a solvent or a mixture of suitable solvents, for example acid amide di-lower alkyl carboxylic acid, such as dimethylformamide, with formamide in the presence of formic acid, at elevated temperatures, for example in the range of 100 to 150 ° C, if required under pressure, in a compound of formula XIII,

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6

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in which R and A 'have the meanings given in the formula XII.

Subsequently, a group L is introduced outgoing, as defined in formula II under conditions analogous to those described above for the transformation of a compound of formula VI in a compound of formula II, as which is obtained a compound of formula II *, which falls within the formula II:

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7

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in formula II *, A 'and R have the meanings given in formula XII, while L means a leaving group, preferably halogen, especially chlorine.

In order to obtain from there a compound of formula II, in which Y is a carbon atom that carries a radical A, which means hydrogen, it is necessary that the saponification and decarboxylation take place according to the methods known (see for example for saponification Chem. Ber. 95, 307-318 (1962), for decarboxylation Helv. Chim. Minutes 33, 130 (1950) oder Bull. Soc. Chim. Fr. 1987, 339-349), for example, under conditions such as described in example 8a2. Thus, a compound of formula is obtained II **,

8

which, in the same way, falls into the formula II, and in which R and L have the meanings given for the compounds of formula I.

It is also possible to decarboxylate a compound of formula XIII, in order to subsequently introduce group L outgoing by said reagents, according to which it is obtained from similarly a compound of formula II **.

The compound of formula IV can be produced from 4,6-dihydroxy-5-nitropyrimidine (Aldrich, Buchs, Switzerland), for example, by reduction with tin (II) chloride according to M. Ishidate et al ., Chem. Pharm . Bull. 8, 137-139 (1960). In the same way, the β-ketoesters of formula IX are known, can be produced by known methods or are commercially available.

Examples

The following examples illustrate the invention, but they are not intended to restrict its scope in any way.

If the opposite is not indicated, all IR spectra in KBr. The NMR classification: *) is based on estimates Melting points are not corrected. The reasons of volume of solvents or eluents are given in proportions of volume (v / v). Unless otherwise indicated, temperatures they are given in degrees Celsius (° C). Unless otherwise stated, The reactions take place at room temperature.

Abbreviations

Anal. calc.

theoretical proportions of the elements in the elementary analysis

CCF

Thin layer chromatography

DMEU

1,3-dimethyl-2-imidazolidinone

DMF

dimethylformamide

Et

ethyl

EtOAc

ethyl acetate

found

proportions found (= measures) of the elements in the elementary analysis:

h

hours)

Hv

high vacuum

conc.

concentrated

I

methyl

Min

minute (s)

EM

mass spectrum

NMR:

nuclear magnetic resonance

RF

reflux (temperature heating of boiling)

TA

room temperature

m.p.

melting point

T

temperature

TBME

tert-butyl methyl ether

THF

tetrahydrofuran (distilled over Na)

9

Example 1 3- {2 '- (4' '- aminophenyl) oxazolo [5,4-d] pyrimidin-7'-ylamino} phenol

0.574 g (1.64 mmol) of 3- {2 '- (4' '- nitrophenyl) oxazolo [5,4-d] pyrimidin-7'-ylamino} phenol together with 1.6 ml of catalyst suspension (Raney nickel ethanolic) in about 20 ml of THF, and stirred overnight in H2 at normal pressure. The solution is filtered by suction and the filtrate is mixed with about 50 ml of H2O, whereby it forms a light brown deposit, which is removed by filtration by suction. A few days later, a brown deposit forms dark in the filtrate. This is extracted by suction. Again, a beige solid precipitates from the filtrate. This one separates and it Dry under high vacuum. m.p .: ~ 285 ° C; 1 H-NMR (300 MHz, DMSO): 9.96, 9.39 (s, NH, OH); 8.41 (s, H-C (5 ')); 7.88 (dd, J = 1.8, 8.7, H-C (3 '')); 7.47 (pseudo t, J = 2.2, H-C (2)); 7.30 (dd, J = 8.1, 1.1, 1H); 7.12 (pseudo t, J = 8.1, H-C (5)); 6.72 (dd, J = 6.9, 1.8, H-C (2``)); 6.48 (m, 1 H); 6.08 (s, NH2).

Example 1st

3- {2 '- (4' '- nitrophenyl) oxazolo [5,4-d] pyrimidin-7'-ylamino} phenol

452 mg (1.64 mmol) of 7-Chloro-2- (4'-nitrophenyl) oxazolo [5,4-d] pyrimidine with 587 mg (5.38 mmol) of 3-aminophenol (Fluka, Buchs, Switzerland) in about 100 ml of n-butanol, and it Heat up to RF for 90 minutes. After cooling to RT, it filter by suction a violet residue. This one is washed with a little of n-butanol and dried at HV. m.p .:> 250 ° C; Anal. calc. for C 17 H 11 N 5 O 4 (349.31): C 58.45, H 3.17, N 20.25, OR 18.32; Found: C 57.89, H 3.36, N 19.88, O 18.19.

The starting material is prepared as follow:

7-Chloro-2- (4'-nitrophenyl) oxazolo [5,4-d] pyrimidine

6.83 g (41.8 mmol) of 5-amino-4,6-dihydroxypyrimidine (prepared from 4,6-dihydroxy-5-nitropyrimidine (Aldrich, Switzerland) is dissolved by reduction with tin (II) chloride according to M. Ishidate et al ., Chem. Pharm. Bull. 8, 137-139 (1960)) in about 100 ml of pyridine abs. and mixed with 9.84 g (52.9 mmol) of 4-nitrobenzoyl chloride, heated to RF for about 1 h under Ar atmosphere, and then concentrated by evaporation at 75 ° C. 75 ml of phosphorus oxychloride are added to the dark red residue and the reaction mixture is heated to RF for 1 h under Ar. After cooling, the reaction mixture is concentrated by evaporation (T <60 ° C) and then added to a NaOAc / ice mixture with constant stirring. The suspension is fixed at pH 5 with NaOAc and filtered by suction. The residue is washed with H2O and EtOH. The residue that is dried in HV is boiled in about 150 ml of EtOH, filtered by suction while it is heated and dried in HV. A brown solid is obtained. Purification by column chromatography (silica gel, ethyl acetate / pentane 90:10-75:25) gives the title compound as colorless needles to pale yellow, mp: 231 ° C.

Example 2 Hydrochloride 7- (3 '' - chloroanilino) -2- (4'-aminophenyl) oxazolo [5,4-d] pyrimidine

1.61 g (4.4 moles) of 7- (3 '' - chloroanilino) -2- (4'-nitrophenyl) oxazolo [5,4-d] pyrimidine in a water bath at RT in about 10 ml of conc. hydrochloric acid. and 10 ml of ethanol. After adding 2.50 g of SnCl2, the water bath up to about 80ºC. After about 100 min, they are added 40 ml conc. Hydrochloric acid and the water bath is removed. Be suction filter the cooled suspension to RT and dry the residue at HV. The residue is suspended again in H2O, left stand, filter by suction and dry the residue in HV. p .: 260-270 ° C (partial decomposition). 1 H-NMR (300 MHz, DMSO): 10.36, (s, NH); 8.50 (s, H-C (5)); 8.16 (m, H-C (2``)); 7.95 (d, J = 8.7, H-C (2 ')); 7.85 (dd, J = 2.9, 1H); 7.34 (pseudo t, J = 8.1, H-C (5``); 7.12 (ddd, J = 6.3, 2, 0.9, 1H); 6.9 (d, J = 8.8, H-C (3 ')).

Example 2nd

7- (3 '' - chloroanilino) -2- (4'-nitrophenyl) oxazolo [5,4-d] pyrimidine

150 mg (0.54 mmol) of 7-Chloro-2- (4'-nitrophenyl) oxazolo [5,4-d] pyrimidine together with 0.17 ml (1.6 mmol) of 3-chloroaniline (Fluka, Buchs, Switzerland) in about 30 ml of n-butanol, and heated to RF for about 2 h. After removing the heating bath, a solid precipitates. Be filter the solid by suction, wash with a little n-butanol and dried to HV. p .: 282-287 ° C. Anal. calc. for C 17 H 10 ClN 5 O 3 (376.76): C 55.52, H 2.74, N 19.04, OR 13.05; found C 55.15, H 3.04, N 18.59, O 13.89.

Example 3 4- {2 '- (4' '- aminophenyl) oxazolo [5,4-d] pyrimidin-7'-ylamino} phenol

350 mg (1.0 mmol) of 4- {2'-4 '' - nitrophenyl) oxazolo [5,4-d] pyrimidin-7'-ylamino} phenol in 100 ml of THF and 20 ml of DMEU, mix with a tip of Raney nickel catalyst spatula (ethanolic suspension), and Stir over the weekend in H2 at normal pressure. Be the resulting suspension is filtered by suction, the filtered and mixed with about 150 ml of H2O. Again the suspension obtained is filtered by suction, the residue is washed with H2O and dried at HV. Again, the crude product dissolves in hot THF and filtered by suction immediately. Be concentrate the filtrate by evaporation and the residue is dried reddish at HV at 150 ° C. m.p .:> 250 ° C. IR: 3446 w, 3311 w, 3194 w, 1618 s, 1509 s, 1483 s, 1439 m, 1322 m, 1312 m, 1267 m, 1225 m, 1171 w, 1080 w (w = "weak" = weak, s = "strong" = strong, m = "medium" = medium).

Example 3rd

4- {2 '- (4' '- nitrophenyl) oxazolo [5,4-d] pyrimidin-7'-ylamino} phenol

2.22 g (8.0 mmol) of 7-Chloro-2- (4'-nitrophenyl) oxazolo [5,4-d] pyrimidine until reflux for 3 h with 2.58 g (23.6 mmol) of 4-aminophenol (Fluka, Buchs, Switzerland) in 350 ml of n-butanol. The suspension is allowed to cool orange-red until TA. Then, it is filtered by suction, and the residue is dried at HV (m.p.> 300 ° C), then Suspend in about 40 ml of 98% EtOH (about 70 ° C), filter again by suction and dried at HV [crystalline, m.p. > 300 ° C]. IR: 3360 w, 3178 w, 1630 m, 1607 m, 1518 m, 1482 w, 1348 m, 1217 m, 1079 w, 1045 w, 855 w, 710 w, 516 w.

Example 4 7- (4 '' - chloroanilino) -2- (4'-aminophenyl) oxazolo [5,4-d] pyrimidine

0.536 g (2.93 mmol) of 7- (4 '' - chloroanilino) -2- (4'-nitrophenyl) oxazolo [5,4-d] pyrimidine with a Raney nickel catalyst spatula tip (ethanolic suspension) in about 15 ml of DMEU and about 75 ml of THF, and stirred for 22 h in H2 at normal pressure, and then filter by suction. The residue is concentrated and mixed with H2O. The suspension thus obtained is filtered again by Suction, dried over HV, dissolved in THF and mixed with MeOH. Be filter the suspension thus obtained by suction. Dries on residue at HV; m.p .: 296-301 ° C.

Example 4th

7- (4 '' - chloroanilino) -2- (4'-nitrophenyl) oxazolo [5,4-d] pyrimidine

1.99 g (7.2 mmol) of 7-Chloro-2- (4'-nitrophenyl) oxazolo [5,4-d] pyrimidine up to RF for 90 min with 2.75 g (21.6 mmol) of 4-Chloroaniline (Fluka, Switzerland) in about 300 ml of n-butanol. After cooling to RT, it is filtered by suction the suspension and wash the residue with a little methanol and a lot of EtOH, dried to HV, then heated in about 400 ml of DMSO and filtered while hot. Scales precipitate from of the filtrate; m.p .: about 300 ° C. 1 H-NMR (300 MHz, DMSO): 10.6 (s, NH); 8.57 (s, H-C (5)); 8.49 (d, J = 8.9, 2H); 8.43 (d, J = 9.0, 2H); 7.98 (d, J = 9.0, H-C (2``)); 7.44 (d, J = 8.8, H-C (3``)).

Additional examples

The following compounds of formula A are produced analogously to the examples and methods above mentioned, using 7-Chloro-2- (3'-nitrophenyl) oxazolo [5,4-d] pyrimidine (for preparation see footnote 10) instead from 7-Chloro-2- (4'-nitrophenyl) oxazolo [5,4-d] pyrimidine. From the compounds of formula A, compounds of formula B by reduction:

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Example 5

10.18, 9.44 (s, NH, OH); 8.49 (s, -H-C (5 '); 7.47 (pseudo t, J = 2.1, 1H); 7.41 (pseudo t, J = 1.9, 1H); 7.39-7.11 (m, 3H); 7.14 (pseudo t, J = 8.1, H-C (5); 6.83 (ddd, J = 8.0, 2.3, 1.0, 1H); 6.52 (ddd, J = 8.1, 2.4, 0.9, H-C (6)); 5.55 (s, NH2).

Example 5th

10.32, 9.45 (s, NH, OH); 8.98 (pseudo t, J = 2.0, H-C (2``)); 8.58 (pseudo d, J = 7.3, 1H); 8.55 (s, H-C (5 ')); 8.50 (d x pseudo t, J = 8.4, 1.2, 1H); 7.97 (pseudo t, J = 8.0, H-C (5``)); 7.49 (pseudo t, J = 2.0, H-C (2)); 7.34 (d x pseudo d, J = 8.0, 1.2, H-C (4)); 7.16 (pseudo t, J = 8.1, H-C (5)); 6.55 (d x pseudo d, J = 7.6, 2.1, H-C (6)).

Example 6

10.51 (s, NH); 8.56 (s, H-C (5)); 8.71 (pseudo t, J = 2.0, H-C (2``)); 7.88 (ddd, J = 8.3, 2.1, 0.9, 1H); 7.43-7.36 (m, 3H); 7.28 (pseudo t, J = 7.8, H-C (5 ')); 7.15 (ddd, J = 8.0, 2.1, 0.9, 1H); 6.84 (ddd, J = 8.0, 2.3, 1.1, 1H); 5.56 (s, NH2).

Example 6th

10.60 (s, NH); 8.96 (pseudo t, J = 1.9, H-C (2 ')); 8.62 (s, H-C (5)); 8.58 (pseudo d, J = 7.7, 1H); 8.49 (ddd, J = 8.3, 2.3, 0.9, 1H); 8.18 (pseudo t, J = 2.0, H-C (2``)); 7.96 (pseudo t, J = 8.0, H-C (5 ')); 7.88 (pseudo d, J = 7.7, H-C (6``)); 7.41 (pseudo t, J = 8.1, H-C (5``)); 7.17 (pseudo d, J = 8.2, H-C (4``)).

Example 7

10.02, 9.04 (s, NH, OH); 8.42 (s, H-C (5 ')); 7.40-7.34 (m, 3H); 7.29-7.20 (m, 2H); 6.91 (d, J = 8.8, 1H); 6.83 (dd, J = 8.0, 1.0, 1H); 5.53 (s, NH2); 3.78 (s, CH 3 O).

Example 7a

10.19, 9.07 (s, NH, OH); 8.95 (pseudo t, J = 1.8, H-C (2``)); 8.57 (pseudo d, J = 7.8, 1H), 8.51-8.47 (m, 2H); 7.96 (t, J = 8.1, H-C (5``)); 7.24 (d, J = 2.6, H-C (6)); 7.24 (dd, J = 8.8, 2.6, H-C (4)); 6.93 (d, J = 8.8, H-C (3)); 3.79 (s, H 3 C).

1) Name: 3- {2 '- (3' '- aminophenyl) oxazolo [5,4-d] pyrimidin-7'-ylamino} phenol; additional purification stage at the end: column chromatography after absorption on 10 g of silica gel applied as a powder, and eluted with CH 2 Cl 2: methanol 100: 0-95: 5.

2) with partial decomposition.

3) Name: 3- {2 '- (3' '- nitrophenyl) oxazolo [5,4-d] pyrimidin-7'-ylamino} phenol:

4) at about 290 ° C, forms platelets which then melts to approximately 307-313 ° C.

5) Name: 7- (3 '' - chloroanilino) -2- (3'-aminophenyl) oxazolo [5,4-d] pyrimidine:

6) Name: 7- (3 '' - chloroanilino) -2- (3'-nitrophenyl) oxazolo [5,4-d] pyrimidine:

7) additional purification step at the end: column chromatography on silica gel, CH2Cl2: methanol
99: 1 - 96: 4.

8) Name: 2-methoxy-5- {2 '- (3' '- aminophenyl) oxazolo [5,4-d] pyrimidin-7'-ylamino} phenol.

9) Name: 2-methoxy-5- {2 '- (3' '- nitrophenyl) oxazolo [5,4-d] pyrimidin-7'-ylamino} phenol.

10) Preparation of 7-chloro-2- (3'- nitrophenyl) oxazolo [5,4-d] pyrimidine :

2.25 g (17.7 mmol) of 5-amino-4,6-dihydroxypyrimidine (for preparation see example 1b)) in about 100 ml of absolute pyridine together with 3.73 g (20.0 mmol) of chloride 3-nitrobenzoyl (Fluka, Buchs, Switzerland), is heated to RF for 1 h in an Ar atmosphere, then it is concentrated by evaporation at 7 ° C and dried at HV. The residue is heated until RF for about 2 h in about 100 ml of oxychloride phosphorus in Ar atmosphere, it is concentrated by evaporation (T <60 ° C), and then added to a mixture of NaOAc / ice while stirring constantly. The suspension is fixed at pH 5 with NaOAc, allowed to stand overnight and filtered by suction the next day. The residue is washed with H2O, subjected to Boil in a lot of ethanol, and filter while hot. Be leave the filtrate for a week in a refrigerator, filter by suction and the residue is dried in HV. Final treatment by column chromatography (ethyl acetate / pentane 1: 0 - 2: 1) gives rise to the title compound: m.p. 144-147 ° C.

11) at about 260 ° C, they form crystals that then melt at approximately 323-325 ° C.

Example 8 4- (chloro-2-fluoroanilino) -6- (4-aminophenyl) furo [2,3-d] pyrimidine

0.95 g (2.5 mmol) of 4- (4-Chloro-2-fluoroanilino) -6- (4-nitrophenyl) furo [2,3-d] pyrimidine in about 50 ml of THF, 2 ml of triethylamine and 2 ml of DMEU, it mixed with a spatula tip of catalyst suspension (nickel of ethanolic Raney) and stir overnight under pressure H2 normal. The suspension is filtered by suction through Celite, it is concentrated by evaporation, mixed with H2O, fixed to pH 10 with a 5% NaOH solution, filtered by suction, and the residue is washed with a lot of H2O. The product is subjected to final treatment by column chromatography (dissolved in acetone and added to the column as a silica gel adsorbate, silica gel, pentane: ethyl acetate = 3: 2, m.p .: 229-232 ° C.

Example 8a

4- (4-Chloro-2-fluoroanilino) -6- (4-nitrophenyl) furo [2,3-d] pyrimidine

1.65 g (5.9 mmol) of 4-chloro-6- (4-nitrophenyl) furo [2,3-d] pyrimidine are heated for about 4 h until boiling with 2.2 ml of 4-chloro- 2-fluoroaniline in 100 ml of 1-butanol. The mixture is allowed to cool and filtered by suction. The residue is washed, successively, with a lot of 1-butanol, methanol and tert-butyl methyl ether, and dried over HV. The crude product is recrystallized from acetic acid. mp:> 250 ° C, 1 H-NMR (500 MHz, DMSO) ^ dagger : 10.0 (s, NH); 8.41 (s, HC (2)); 8.36 (d, J = 9.1, HC (2 ')); 8.08 (d, J = 9.0, HC (3 ')); 7.82 (pseudo t, J = 8.6, HC (6 '')); 7.78 (s, HC (5)); 7.57 (dd, J = 10.4, 2.4, HC (3 '')); 7.35 (ddd, J = 8.6, 2.4, 1.1, HC (5``)).

The starting material is prepared as follow:

8a1: 4-Chloro-6- (4-nitrophenyl) furo [2,3-d] pyrimidine

13.5 g of are heated 4-hydroxy-6- (4-nitrophenyl) furo [2,3-d] pyrimidine for 1.5 h at RF in about 200 ml of phosphorus oxychloride (Fluka, Buchs). Then, the mixture of the mixture is allowed to rest in the open air. reaction for 3 days, and then added to 4 kg of ice. Be filter the suspension by suction and wash with a lot of H2O. The product is sublimated at about 200 ° C and about 0.1 mbar. He Sublimated consists of lemon yellow non-crystalline needles: m.p .: from 245 ° C (decomposition). 1 H-NMR (300 MHz, DMSO): 8.91 (s, H-C (2)); 8.40, 8.31 (d, J = 9.2, H-C (2 ', 3')); 8.09 (s, H-C (5)).

8a2: 4-hydroxy-6- (4-nitrophenyl) furo [2,3-d] pyrimidine

21 g of acid dissolve 4-hydroxy-6- (4-nitrophenyl) furo [2,3-d] pyrimidine-5-carboxylic in about 200 ml of pyridine while heating, and subsequently they are concentrated by evaporation at 80 ° C. Be heat the residue to 190 ° C for 1 h, with a stream nitrogen constant, in 500 ml of quinoline, which has dried on magnesium sulfate, with 1 g of Cu 2 O (Aldrich, Buchs). Be let the reaction mixture cool and add to 1 liter of acid 2.5 M hydrochloric, stirred and filtered by suction. He washes the residue with conc. of ammonia and with H2O. Dries the dark brown residue at HV: m.p .:> 350 ° C.

8a3: acid 4-hydroxy-6- (4-nitrophenyl) furo [2,3-d] pyrimidine-5-carboxylic

3.0 g (9.1 mmol) of boil are boiled ethyl acid ester 4-hydroxy-6- (4-nitrophenyl) furo [2,3-d] pyrimidine-5-carboxylic for 50 min in about 50 ml of sodium hydroxide solution at 5% The reaction mixture is filtered by suction while It is hot and the residue is discarded. [In order to get the 4-hydroxy-6- (4-nitrophenyl) furo [2,3-d] pyrimidine-5-carboxylate  of sodium, the cold filtrate is filtered by suction (after cool, needles form) on ice and wash with a little water frost. The needles are dried at HV. m.p. > 250 ° C (decomposition).]. After cooling, the filtrate is carefully adjusted to pH 1 with acid conc. hydrochloric (a precipitate forms). Filtration by suction and drying of the residue to HV gives rise to the compound of title as a solid, which melts at 300-302 ° C (decomposition at the melting point):

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8a4: ethyl ester of acid 4-hydroxy-6- (4-nitrophenyl) furo [2,3-d] pyrimidine-5-carboxylic

7.34 g diethyl acid ester of 2-amino-5- (4-nitrophenyl) furan-3,4-dicarboxylic for 14 h at 140 ° C in N 2 in 40 ml of formamide, 20 ml of DMF and 10 ml of 98-100% formic acid. The reaction mixture by an ice bath. Then, it is extracted by filtration a viscous mass and wash, first of all, with propan-2-ol and then with hexane. The residue is dried in HV, heated in 200 ml of EtOH and filtered by suction while it is hot. Drying the residue at HV gives rise to the title compound: p .: 279-282 ° C.

8a5: diethyl acid ester 2-amino-5- (4-nitrophenyl) furan-3,4-dicarboxylic

105 g (0.39 mol, 1 eq) of ester are dissolved ethyl acid 4-nitrobenzoyl-chloroacetic acid in 600 ml of THF. To this solution are added, in a water bath (T = 35 ° C), in parts, 49.4 g (0.37 mol) of acid ethyl ester finely ground sodium cyanoacetic acid (preparation: Chem. Ber. 1962, 95, 307-318). It is stirred overnight (in N2), is completely concentrated by evaporation, and is extract with H2O and CH2Cl2. The phase of CH 2 Cl 2 combined with H 2 O, finally dried over MgSO4 and free of solvent. Crystallization from toluene gives rise to the title compound, m.p .: 174-177 ° C.

8a6: ethyl acid ester 4-nitrobenzoyl-chloroacetic acid (ester ethyl acid 2-Chloro-3- (4-nitrophenyl) -3-oxo-propanoic acid)

Described in J. Heterocycl. Chem. 1985, 32, 1621-1630 (and bibliography thereof). Simplified preparation: 100.2 g (0.42 mol) of 4-nitrobenzoyl acetic acid ethyl ester (Acros, Belgium) are suspended in 350 ml of toluene and mixed with 45 ml (75 g; 0.55 mol) of SO_ {Cl} {2}. Stirring is carried out for 1 h at 80 ° C under reduced pressure (about 900 hPa). Subsequently, the temperature and pressure are gradually reduced. The residue is quenched with ice water and extracted several times with toluene. The organic phase is washed with H2O and finally neutralized with a sat solution. NaHCO3, dried (MgSO4) and concentrated to form the compound of
Title.

The following derivatives are prepared in a manner analogous to that described in example 8:

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Example 13 4- (1-R-phenylethylamino) -6- (3-aminophenyl) furo [2,3-d] pyrimidine

1.47 g (4.1 mmol) of 4- (1R-phenylethylamino) -6- (3-nitrophenyl) furo [2,3-d] pyrimidine in about 50 ml of THF, they are mixed with a spatula tip of Raney's nickel suspension, stirred overnight in H2 at normal pressure, it is filtered by suction through Celite, it the filtrate is concentrated by evaporation, taken to TBME and extract with H2O. The organic phase is dried over MgSO4, concentrated by evaporation and dried at HV. The product is taken at CH 2 Cl 2, it is extracted with hydrochloric acid semi-concentrated, the aqueous phase is separated, neutralize with sat. of NaHCO_ {3} and it is extracted again with CH 2 Cl 2. Drying of the organic phase over MgSO4 and concentration by evaporation gives rise to the compound of Title. m.p .: 64-84 ° C. IR: 3340 m a, 3028 w, 2972 w, 1600 s, 1570 m, 1491 m, 1466 m, 1352 m, 1303 m, 1228 w, 1141 m, 941 w, 776 m, 700 m, 551 w. EM-IE ("EI-MS"): 330 (M +).

The starting material is prepared as follow:

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13a: 4- (1R-phenylethylamino) -6- (3-nitrophenyl) furo [2,3-d] pyrimidine

2.43 g (8.8 mmol) of 4-chloro-6- (3-nitrophenyl) furo [2,3-d] pyrimidine for 2.5 h until boiling with 4.2 ml of R - (+) -? -Methylbenzylamino (Fluka, Buchs, [3886-69-9]) in close 75 ml of 1-butanol. It is concentrated by evaporation the solution (80 ° C, 100 mbar), mixed with 100 ml of H 2 O and 300 ml of TBME and stirred, thereby forming a precipitate. The two phase mixture is filtered by suction and Dry the residue in HV. Recrystallization in EtOH gives rise to title compound, m.p. 163-165 ° C.

The starting material is prepared as follow:

13b: 4-chloro-6- (3-nitrophenyl) furo [2,3-d] pyrimidine

11 g of are heated 4-hydroxy-6- (3-nitrophenyl) furo [2,3-d] pyrimidine for 4 h until RF in about 340 ml of phosphorus oxychloride. Then, the reaction mixture is allowed to stand overnight and then it is added to 5 kg of dried ice. It is filtered by suction the resulting suspension and wash with a lot of H2O. Be Dry the residue in HV and sublimate to about 200 ° C; p .: 196-205 ° C.

The starting material is prepared as follow:

13c: 4-hydroxy-6- (3-nitrophenyl) furo [2,3-d] pyrimidine

18.4 g of the acid are placed 4-hydroxy-6- (3-nitrophenyl) furo [2,3-d] pyrimidine-5-carboxylic in about 200 ml of quinoline, and heat for 20 min until 200-220 ° C in a constant stream of N 2. Then, 0.7 g of Cu 2 O are added. After 2 hours, 0.4 is added additional g of Cu 2 O. 1 hour later, another tip of Cu 2 O spatula and the temperature is reduced. The next day, The reaction mixture is mixed with 0.5 liters of 2.5 M HCl, dilute with H2O, stir, let stand for 8 h and filter by suction. The residue is washed with conc. Ammonia. Y with a lot of H2O. The basic filtrate is acidified with conc. HCl, it is filtered by suction and washed with a lot of H2O. Used the gross product of the two wastes directly without treatment additional end m.p .:> 300 ° C. IR: 3091 w, 2853 w, 1670 ss, 1593 w, 1527 s, 1496 w, 1475 w, 1373 w, 1348 s, 1297 w, 1202 m, 938 m, 900 m, 783 w, 740 w, 703 w, 622 w.

The starting material is prepared as follow:

13d: acid 4-hydroxy-6- (3-nitrophenyl) furo [2,3-d] pyrimidine-5-carboxylic

0.95 g (3.2 mmol) of ethyl ester are placed of the acid 4-hydroxy-6- (3-nitrophenyl) furo [2,3-d] pyrimidine-5-carboxylic in 30 ml of a 5% sodium hydroxide solution and heat for 30 min until 100 ° C. The reaction mixture is filtered while It is hot and the filtrate is cooled to RT. Subsequently adjust the pH of the solution to 1 with conc. hydrochloric acid, while it cools. A brown deposit is formed, which is removed by filtration by suction and dried at HV m.p .:> 300 ° C. IR: 3448 w, 3237 m, 3088 w, 1752 s, 1734 s, 1672 s, 1531 s, 1474 m 1407 m 1381 m, 1346 s, 1241 m, 1211 m.

The starting material is prepared as follow:

13e: acid ethyl ester 4-hydroxy-6- (3-nitrophenyl) furo [2,3-d] pyrimidine-5-carboxylic

72.9 g diethyl acid ester is stirred 2-amino-5- (3-nitrophenyl) furan-3,4-dicarboxylic for about 23 h at 140 ° C in N 2 in 200 ml of formamide, 100 ml of DMF and 40 ml of 98-100% formic acid. After cooling the solution, the reaction mixture is diluted with H2O, Let stand for 8 h and filter by suction. Dries on residue to HV, boil in 300 ml of acetonitrile, se filter by suction, wash with iced acetonitrile and dry to HV This second residue is boiled in 200 ml of chloride of methylene, it is filtered by suction while it is hot, it wash with methylene chloride and dry to HV. The residue obtained contains the product; m.p .: 212-220 ° C. IR: 3528 w, 3246 m, 3092 m, 2985 w, 1936 w, 1721 s, 1589 m, 1543 s, 1482 m, 1429 w, 1378 s, 1352 s, 1323 m, 1287 m, 1234 m, 1196 m, 1076 m, 1042 s.

In the product thus obtained, it is obtained as acid amide byproduct 4-hydroxy-6- (3-nitrophenyl) furo [2,3-d] pyrimidin-5-carboxylic. This is obtained in pure form by analysis by recrystallization from DMF; m.p .: about 380 ° C (decomposition) IR: 3338 m, 3180-2810 w (multiplet), 1708 s, 1676 s, 1589 w, 1560 m, 1526 s, 1406 w, 1348 s, 1220 w, 1105 w, 1081 w, 1041 w, 920 w, 899 w, 880 w, 803 w, 740 w, 676 w.

The starting material is prepared as follow:

13f: diethyl acid ester 2-amino-5- (3-nitrophenyl) furan-3,4-dicarboxylic

25 g of acid ethyl ester are placed (3-nitrophenyl) -3-oxopropanoic (0.10 moles; Acros, Belgium) in 300 ml of toluene. 12.8 ml are added of sulfuryl chloride (0.15 mol) to this suspension at RT. After 10 min additional, the reaction is quenched with 150 ml of H2O. Be extract the organic phase with sodium hydrogen carbonate solution sat. until the aqueous phase has a pH of> 7. Later extract the organic phase again with H2O, dry with sulfate of magnesium and filtered by suction. The toluene evaporates. Be place 180 g of the oil obtained in 400 ml of distilled THF on Na and in Ar. 79.6 g of sodium cyanoacetic ester powder are added fine (0.59 mol) in parts to this solution while cooling (preparation: Chem. Ber. 1962, 95, 307-318). After stir for 3 h at 25 ° C, THF is removed, the residue is taken oily to CH2Cl2 and extracted with H2O. The organic phase with magnesium sulfate, filtered by suction and the solvent is evaporated. An orange oil is obtained, which it crystallizes from p-xylene. p .: 169 ° C.

The following derivatives are also produced at starting from A (example 13a) analogously to example 8.

17

18

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19

The following derivatives can be produced from analogously to the previous examples:

twenty

twenty-one

22

2. 3

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24

25

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The starting material is prepared as follow:

a) Methyl acid ester 4-benzyloxycarbonylacetyl-benzoic

In an atmosphere of N2, 9.5 g of MgCl 2 (100 mmol, dried at 130 ° C at HV) in 100 ml of CH 2 Cl 2 and mixed, while cooling on ice, with 25.0 g of benzyl tert-butylmalonate (100 mmol) and 27.9 ml of triethylamine (200 mmol). After 15 min, 19.8 g are added of acid methyl ester 4-Chlorocarbonyl-Benzoic (100 mmoles) dissolved in 30 ml of CH2Cl2 over 30 minutes, and stir overnight at RT. Mix the mixture of reaction with ice water, the aqueous phase is separated and extracted with CH 2 Cl 2. The organic phase is washed twice with a 5% citric acid solution and brine, dried (Na 2 SO 4), and is concentrated by evaporation (50 g of a oil). The residue is dissolved in 400 ml of formic acid and stir for 2 days at RT. The formic acid is evaporated in vacuo. Be dissolve the evaporation residue in EtOAc and solution of Diluted NaHCO3, the aqueous phase is separated and extracted twice more with EtOAc. The organic phases are washed with a solution of NaHCO 3, H 2 O and brine, dried (Na 2 SO 4) and dried concentrate by evaporation. The residue is dissolved in toluene boiling, it is partially concentrated and cooled to RT. Be a precipitation formed is filtered off and discarded. Finally, the title compound was obtained from the filtrate. cooling it briefly in carbonic snow, filtering the crystals formed and washing with cold toluene: m.p .: 71 ° C.

b) Methyl acid ester 4- (benzyloxycarbonyl-chloro-acetyl) -benzoic acid

4.0 g (12.8 mmol) of methyl ester are mixed of the acid 4-benzyloxycarbonylacetyl-benzoic acid, dissolved in 40 ml of toluene, with 19.2 ml of a solution of 1 M SO 2 Cl 2 in CH 2 Cl 2 and stirred for 30 min to TA. At 0 ° C, water is added and the aqueous phase is separated and extracted two times with EtOAc. The organic phases are washed twice with NaHCO 3 sat. solution, H2O and brine, dried (Na 2 SO 4) and are concentrated by evaporation. The column chromatography (SiO2; hexane / EtOAc 9: 1 → 4: 1; Gross product dissolved in CH2Cl2) resulted in title compound as an oil: MS: [M + 1] + = 347; CCF (hexane / EtOAc 4: 1) R f = 0.19.

c) Ester 3-methyl-4-benzyl of the acid 2-amino-5- (4-methoxycarbonyl-phenyl) -furan-3,4-dicarboxylic acid

In an atmosphere of N2, 785 mg (2.28 is stirred mmoles) of methyl acid ester 4- (benzyloxycarbonyl-chloro-acetyl) -benzoic acid, dissolved in 3.5 ml of THF, at 35 ° C. To these are added by parts 284 mg (2.35 mmol) of sodium cyanoacetic acid methyl ester fine powder (preparation: Chem. Ber. 1962, 95, 307-318). After 5 h, the mixture is filtered, concentrate the filtrate by evaporation and bring the residue to H2O and EtOAc. The aqueous phase is separated and extracted twice with EtOAc The organic phases are washed with H2O and brine, Dry (Na2SO4) and concentrate by evaporation. The column chromatography (SiO2; CH2Cl2 → CH 2 Cl 2 / acetone 39: 1) and crystallization from toluene in boiling gives rise to the title compound: m.p .: 138-139 ° C; 1 H-NMR (CDCl 3): 7.92 (d, 2H), 7.50 (d, 2H), 7.42 (m, 2H), 7.37 (m, 3H), 5.70 (s, H 2 N), 5.38 (s, 2H), 3.91 (s, H 3 C), 3.64 (s, H 3 C).

d) Benzyl acid ester 6- (4-Methoxycarbonyl-phenyl) -4-oxo-3,4-dihydro-furo [2,3-d] pyrimidine-5-carboxylic acid

Under an atmosphere of N2, 100 mg dissolve (0.25 mmol) ester 3-methyl-4-benzyl of the acid 2-amino-5- (4-methoxycarbonyl-phenyl) -furan-3,4-dicarboxylic acid  in 1.25 ml of a mixture of HCONH2, DMF and HCOOH (4: 2: 1) and stir for 139 h at 120 ° C. The DMF evaporates in vacuo. The boiling methanol recrystallization gives the compound of title: m.p .: 248-249 ° C; MS: [M + 1] + = 405; 1 H-NMR (DMSO-d 6): 12.9 (s, 1H), 8.26 (s, 1H), 7.98 (d, 2H), 7.80 (d, 2H), 7.47 (m, 2H), 7.35 (m, 3H), 5.38 (s, 2H), 3.88 (s, H3 C). Among other impurities, the filtrate contains acid 6- (4-Methoxycarbonyl-phenyl) -4-oxo-3,4-dihydro-furo [2,3-d] pyrimidine-5-carboxylic: MS: [M + 1] + = 315.

e) Acid 6- (4-Methoxycarbonyl-phenyl) -4-oxo-3,4-dihydro-furo [2,3-d] pyrimidine-5-carboxylic acid

Catalytic hydrogenation of the benzyl ester of the acid 6- (4-Methoxycarbonyl-phenyl) -4-oxo-3,4-dihydro-furo [2,3-d] pyrimidine-5-carboxylic acid Give the title compound.

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Example 38

Rigid capsules : 5000 capsules, each comprising 0.25 g of one of the compounds of formula I mentioned in the preceding examples, are prepared as follows:

Composition

beginning active 1250 g talcum powder 180 g Wheat starch 120 g magnesium stearate 80 g lactose 20 g

Preparation procedure : said substances are sprayed and passed through a sieve with a mesh width of 0.6 mm. Gelatin capsules are filled with 0.33 g portions of the mixture using a capsule filling machine.

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Example 39

Soft capsules : 5000 soft gelatin capsules, each comprising 0.05 g of one of the compounds of formula I mentioned in the preceding examples, are prepared as follows:

Composition

beginning active 250 g PEG 400 one liter Tween 80 1 liter

Preparation procedure : The active substance sprayed in PEG 400 (polyethylene glycol with M r between about 380 and about 420, Fluka, Switzerland) and Tween® 80 (polyoxyethylene sorbitan monolaurate, Atlas Chem. Ind., Inc., Is suspended. US of America, supplied by Fluka, Switzerland) and ground in a wet sprayer to produce a particle size of about 1 to 3 µm. Then 0.43 g portions of the mixture are introduced into soft gelatin capsules using a capsule filled machine.

Claims (17)

1. Compound of formula I 27 in which X means or nitrogen, or a carbon atom that carries a radical TO; A means hydrogen or -COOW, in which W is hydrogen or alkyl, aryl, heterocyclyl or cycloalkyl, as which of these radicals is unsubstituted or replaced; Y is NR ', S or O, according to which R' means hydrogen or alkyl; R means aryl, heterocyclyl, cycloalkyl, aryl-alkyl, heterocyclyl-alkyl or cycloalkyl-alkyl, according to which each of these radicals are unsubstituted or substituted; or is COOR ', COR' or CONR'R '', in which R 'and R' ', independently of each other, are hydrogen or alkyl, aryl, heterocyclyl, cycloalkyl, aryl-alkyl, heterocyclyl-alkyl or cycloalkyl-alkyl, according to which each of these radicals are unsubstituted or substituted; Y Q is aryl, aryl-alkyl, heterocyclyl, heterocyclyl-alkyl, cycloalkyl or cycloalkyl-alkyl, which are respectively not substituted or substituted; or a salt thereof. 2. Compound of formula I according to claim 1, wherein X either means nitrogen, or means a carbon atom that carries a radical A; A means hydrogen or -COOW, in which W means alkyl or hydrogen; Y is NR ', S or O, according to which R' means hydrogen or alkyl; R means aryl, heterocyclyl, cycloalkyl, aryl-alkyl, heterocyclyl-alkyl or cycloalkyl-alkyl, according to which each of these radicals are unsubstituted or substituted; or is COOR ', COR' or CONR'R '', in which R 'and R' ', independently of each other, are hydrogen or alkyl, aryl, heterocyclyl, cycloalkyl, aryl-alkyl, heterocyclyl-alkyl or cycloalkyl-alkyl, according to which each of these radicals are unsubstituted or substituted; Y Q is aryl, aryl-alkyl lower or heterocyclyl, which are respectively unsubstituted or substituted; or a salt thereof. 3. Compound of formula I according to claim 1, wherein X either means nitrogen, or means a carbon atom that carries a radical A; A means hydrogen or -COOW, in which W means alkyl or hydrogen; Y is NR ', S or O, according to which R' means hydrogen or alkyl; R means aryl; Y Q is aryl, aryl-alkyl lower or heterocyclyl, which are respectively unsubstituted or substituted; or a salt thereof. 4. Compound of formula I according to claim 1, wherein X either means nitrogen, or means a carbon atom that carries a radical A; A means hydrogen or -COOW, in which W means alkyl or hydrogen; R means aryl; Y Q is aryl, aryl-alkyl lower; or a salt thereof. 5. Compound of formula I according to claim 1, wherein X either means nitrogen, or means a carbon atom that carries a radical A; A means hydrogen; R means aryl; and Q means aryl, aryl-lower alkyl or heterocyclyl; or a salt thereof; according to which aryl is phenyl, naphthyl, fluorenyl or phenanthrenyl, which are respectively unsubstituted or substituted by up to three substituents selected from amino; lower alkylamino; N, N-di-lower alkylamino; amino-lower alkyl; lower alkylamino-lower alkyl; N, N-di-lower alkylamino-lower alkyl; lower alkanoylamino; halogen; lower alkyl; lower alkenyl; phenyl; naphthyl; halogen-lower alkyl; hydroxyl; lower alkoxy; lower alkenyloxy; phenyl-lower alkoxy; lower alkanoyloxy; carbamyl lower alkoxy; lower carboxy-alkoxy; phenyl-lower alkoxycarbonyl-lower alkoxy; mercapto; nitro; carboxyl; lower alkoxycarbonyl; phenyl-lower alkoxycarbonyl; cyano; C 8 -C 12 alkoxy; carbamoyl; lower alkylcarbamoyl; N, N-di-lower alkylcarbamoyl; N-mono or N, N-diphenyl-lower alkylcarbamoyl; lower alkanoyl; phenyloxy; halogen-lower alkyloxy; lower alkoxycarbonyl; lower alkylpiperazinylcarbonyl; morpholinylcarbonyl; lower alkylpiperazinyl-lower alkyl; lower morpholinyl alkyl; lower alkyl mercapto; halogen lower alkylmercapto; hydroxy lower alkyl; lower alkanesulfonyl; halogen-lower alkanesulfonyl; phenylsulfonyl; dihydroxyboro; lower alkylpyrimidinyl; oxazolyl; lower alkyldioxolanyl; pyrazolyl; lower alkylpyrazolyl; lower alkylenedioxy attached to two adjacent carbon atoms; pyridyl; piperazinyl; lower alkylpiperazinyl; morpholinyl; phenylamino or phenyl-lower alkylamino either unsubstituted or substituted on the phenyl moiety by halogen, lower alkyl, hydroxy, lower alkanoyloxy, lower alkoxy, carboxyl, lower alkoxycarbonyl, carbamoyl, lower N-alkylcarbamoyl, N, N-lower dialkylcarbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N, N-di-lower alkylamino or trifluoromethyl; or a radical of formula R 3 -S (O) m -, wherein R 3 is lower alkyl and m is 0,
1 or 2. 6. Compound of formula I according to claim 1, wherein X either means nitrogen, or means a carbon atom that carries a radical A; A means hydrogen; R means aryl; and Q means aryl, aryl-lower alkyl or heterocyclyl; or a salt thereof; according to which aryl is phenyl, naphthyl, fluorenyl or phenanthrenyl, which are respectively unsubstituted or substituted by up to three substituents selected from amino; lower alkylamino; N, N-di-lower alkylamino; lower alkanoylamino; halogen; lower alkyl; alkenyl lower; phenyl; naphthyl; halogen-alkyl lower; hydroxyl; lower alkoxy; lower alkenyloxy; phenyl-lower alkoxy; lower alkanoyloxy; carbamyl lower alkoxy; lower carboxy-alkoxy; phenyl-alkoxycarbonyl lower-lower alkoxy; mercapto; nitro; carboxyl; lower alkoxycarbonyl; phenyl-lower alkoxycarbonyl; cyano; alkoxy C 8 -C 12; carbamoyl; alkylcarbamoyl lower; N, N-di-alkylcarbamoyl lower; N-monkey or N, N-diphenyl alkylcarbamoyl lower; lower alkanoyl; phenyloxy; halogen-lower alkyloxy; alkoxycarbonyl lower; lower alkyl mercapto; halogen lower alkylmercapto; hydroxy lower alkyl; lower alkanesulfonyl; halogen-lower alkanesulfonyl; phenylsulfonyl; dihydroxyboro; lower alkylpyrimidinyl; oxazolyl; lower alkyldioxolanyl; pyrazolyl; lower alkylpyrazolyl; lower alkylenedioxy attached to two adjacent carbon atoms; pyridyl; piperazino; phenylamino or phenyl-alkylamino lower or unsubstituted or substituted on the phenyl moiety by halogen, lower alkyl, hydroxyl, lower alkanoyloxy, lower alkoxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N, N-lower dialkylcarbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N, N-di-lower alkylamino or trifluoromethyl; or a radical of formula R 3 -S (O) m -, in which R 3 it is lower alkyl and m is 0, 1 or 2. 7. Compound of formula I according to claim 1, wherein X either means nitrogen, or a carbon atom that carries a radical A; in which A means hydrogen; R is phenyl which is substituted by nitro, amino, lower alkylpiperazinylcarbonyl, morpholinyl carbonyl, N, N-dialkylcarbamoyl lower, N, N-di-alkylamino lower-lower alkyl, alkylpiperazinyl lower-lower alkyl or morpholinyl lower alkyl; Y Q is benzyl, phenylethyl; phenyl that is not substituted or substituted by one or more radicals, which, independently of each other, they are selected from hydroxyl, lower alkyl, lower alkoxy and halogen; pyridyl that is substituted by hydroxyl or lower alkoxy; or indole that is substituted by halogen and lower alkyl; or a salt thereof. 8. Compound of formula I according to claim 1, wherein X either means nitrogen, or means a carbon atom that carries a radical A; A means hydrogen; R is phenyl which is substituted by nitro or Not me; and Q is benzyl, phenylethyl; or phenyl that is unsubstituted or replaced by one or more radicals, which, independently of the one on the other, they are selected from hydroxyl, lower alkoxy, especially methoxy, and halogen, especially fluorine, chlorine or bromine, or a salt thereof. 9. Compound of formula I according to claim 1, wherein X either means nitrogen, or means a carbon atom that carries a radical A; A means hydrogen; R is phenyl which is substituted by amino; especially 4-aminophenyl; and Q is benzyl, phenylethyl or phenyl, which is replaced by one or more radicals, which, independently from each other, they are selected from hydroxyl, lower alkoxy, especially methoxy, and halogen, especially fluorine, chlorine or bromine, or a salt thereof. 10. Compound according to one of the claims 1 to 9, in which X means nitrogen. 11. Compound according to one of the claims 1 to 9, in which X means a group CH. 12. Compound according to one of the claims 1 to 11, in which Y is NH or O. 13. Compound of formula I according to claim 1, selected from the group comprising 3- {2 '- (4' '- aminophenyl) oxazolo [5,4-d] pyrimidin-7'-ylamino} phenol; 3- {2 '- (4' '- nitrophenyl) oxazolo [5,4-d] pyrimidin-7'-ylamino} phenol; dihydrochloride 7- (3 '' - chloroanilino) -2- (4'-aminophenyl) oxazolo [5,4-d] pyrimidine; 7- (3 '' - chloroanilino) -2- (4'-nitrophenyl) oxazolo [5,4-d] pyrimidine; 4- {2 '- (4' '- aminophenyl) oxazolo [5,4-d] pyrimidin-7'-ylamino} phenol: 4- {2 '- (4' '- nitrophenyl) oxazolo [5,4-d] pyrimidin-7'-ylamino} phenol: 7- (4 '' - chloroanilino) -2- (4'-aminophenyl) oxazolo [5,4-d] pyrimidine; 7- (4 '' - chloroanilino) -2- (4'-nitrophenyl) oxazolo [5,4-d] pyrimidine; 3- {2 '- (3' '- aminophenyl) oxazolo [5,4-d] pyrimidin-7'-ylamino} phenol; 3- {2 '- (3' '- nitrophenyl) oxazolo [5,4-d] pyrimidin-7'-ylamino} phenol; 7- (3 '' - chloroanilino) -2- (3'-aminophenyl) oxazolo [5,4-d] pyrimidine; 7- (3 '' - chloroanilino) -2- (3'-nitrophenyl) oxazolo [5,4-d] pyrimidine; 2-methoxy-5- {2 '- (3' '- aminophenyl) oxazolo [5,4-d] pyrimidin-7'-ylamino} phenol; 2-methoxy-5- {2 '- (3' '- nitrophenyl) oxazolo [5,4-d] pyrimidin-7'-ylamino} phenol. 4- (4-Chloro-2-fluoranilino) -6- (4-aminophenyl) furo [2,3-d] pyrimidine; 4- (4-Chloro-2-fluoranilino) -6- (4-nitrophenyl) furo [2,3-d] pyrimidine; 4- (3-Chloroanilino) -6- (4-aminophenyl) furo [2,3-d] pyrimidine; 4- (3-Chloroanilino) -6- (4-nitrophenyl) furo [2,3-d] pyrimidine; 4- (3-hydroxy-4-methoxyanilino) -6- (4-aminophenyl) furo [2,3-d] pyrimidine; 4- (3-hydroxy-4-methoxyanilino) -6- (4-nitrophenyl) furo [2,3-d] pyrimidine; 4- (3-hydroxy-4-methylanilino) -6- (4-aminophenyl) furo [2,3-d] pyrimidine; 4- (3-hydroxy-4-methylanilino) -6- (4-nitrophenyl) furo [2,3-d] pyrimidine; 4- (3-aminoanilino) -6- (4-aminophenyl) furo [2,3-d] pyrimidine; 4- (3-aminoanilino) -6- (4-nitrophenyl) furo [2,3-d] pyrimidine; 4- (1 R-phenylethylamino) -6- (3-aminophenyl) furo [2,3-d] pyrimidine; Y 4- (1 R-phenylethylamino) -6- (3-nitrophenyl) furo [2,3-d] pyrimidine; or a salt thereof. 14. Pharmaceutical preparation, comprising a compound of formula I, a pharmaceutically acceptable salt of same, according to one of claims 1 to 13, and at least one pharmaceutically acceptable vehicle. 15. Compound of formula I, or salt pharmaceutically acceptable thereof, according to any one of the claims 1 to 13 for use in therapeutic treatment or diagnosis of the human or animal body. 16. Use of a compound of formula I. 28 in which X means or nitrogen, or a carbon atom that carries a radical TO; A means hydrogen or -COOW, in which W is hydrogen or alkyl, aryl, heterocyclyl or cycloalkyl, as which of these radicals is unsubstituted or replaced; Y is NR ', S or O, according to which R' means hydrogen or alkyl; R means aryl, heterocyclyl, cycloalkyl, aryl-alkyl, heterocyclyl-alkyl or cycloalkyl-alkyl, according to which each of these radicals are unsubstituted or substituted; or is COOR ', COR' or CONR'R '', in which R 'and R' ', independently of each other, are hydrogen or alkyl, aryl, heterocyclyl, cycloalkyl, aryl-alkyl, heterocyclyl-alkyl or cycloalkyl-alkyl, according to which each of these radicals are unsubstituted or substituted; Y Q is aryl, aryl-alkyl, heterocyclyl, heterocyclyl-alkyl, cycloalkyl or cycloalkyl-alkyl, which are respectively not substituted or substituted; or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical preparation for the treatment of diseases associated with altered regulation of angiogenesis, and / or for the treatment of benign tumors or malignant 17. Process for the preparation of a compound of formula I illustrated in claim 1, characterized in that (a) a compound of formula II 29 in which X and R have the meanings given for a compound of formula I in the claim 1 and L means a leaving group, it is made react with an amine, a phenol or a thiol of formula III, (III) Q-YH in which Q has the meanings given for the compounds of formula I and Y is NR ', S or O, as which R 'means hydrogen or alkyl; in which, if it were necessary, the functional groups present in a compound of formula II and / or III, which should not take part in the reaction, are present in protected form, and the protective groups that are present are separated; and, if desired, a compound of formula I that obtainable it becomes a different compound of formula I; a free compound of formula I that can be obtained becomes a salt; a salt that can be obtained from a compound of formula I is convert to another salt or the free compound of formula I; and / or mixtures isomers that can be obtained from compounds of formula I are separated in the isomers individual.